Polymeric adhesive for anchoring compliant materials to another surface

ABSTRACT

Methods, compositions, and kits for adhering polymers and other materials to another material, and in particular to bone or bone-like structures or surfaces. A composition of matter includes a urethane dimethacrylate-methyl methacrylate copolymer with a plurality of first polymer regions based on urethane dimethacrylate and a plurality of second polymer regions based on methyl methacrylate. The method includes placing an orthopedic joint implant having an attachment surface in a joint space, applying a first non-urethane-containing precursor, a second urethane-containing precursor, and a initiator to the attachment surface; contacting the first and second precursors and the initiator with the joint surface; and copolymerizing the first and second precursors and forming an adhesive copolymer and attaching the implant to the joint.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/877,884, filed Oct. 7, 2015, which is a continuation of U.S. patentapplication Ser. No. 13/573,788, filed Oct. 3, 2012, Publication No.US-2013-0103157-A1, which claims the benefit of U.S. Provisional PatentApplication No. 61/542,740, filed Oct. 3, 2011, and to U.S. ProvisionalPatent Application No. 61/672,203, filed Jul. 16, 2012. Each of which isherein incorporated by reference in its entirety.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

FIELD

The present invention pertains to methods, compositions, and kits formaking and using an adhesive copolymer.

BACKGROUND

The art has described semi- and fully interpenetrating polymer networks(IPNs) for use in a variety of applications. For example, U.S.application Ser. No. 12/499,041 filed Jul. 7, 2009, U.S. applicationSer. No. 13/219,348 filed Aug. 26, 2011, and U.S. application Ser. No.13/347,647 filed Jan. 10, 2012 (all of which are incorporated byreference herein) describe IPNs formed from hydrophobic and hydrophilicpolymer for use, e.g., in orthopedic applications. U.S. application Ser.No. 13/219,348 also describes how to increase the adhesive properties ofsuch IPNs and the articles they are made from and gives some examples ofattachment of such articles to, e.g., bones or bone-like structures.

U.S. application Ser. No. 12/409,359 (filed Mar. 23, 2009 andincorporated by reference herein) describes the use of polyurethanepolymers to adhere hydrated polymers (such as hydrogels and hydrogelcomposites) to mammalian bone or bone-like structures.

SUMMARY OF THE DISCLOSURE

The present invention relates in general to methods, kits, andcompositions for adhering two substances together. One aspect takesadvantage of the physical and chemical properties of a polymer toachieve the goal of high mechanical strength in addition to otherdesirable properties. The invention also relates to the use of apolymer, such as a polyurethane-based copolymer, to attach a medicalimplant to a joint.

One aspect of the invention provides a composition of matter including aurethane dimethacrylate-methyl methacrylate copolymer having a pluralityof first polymer regions based on urethane dimethacrylate and aplurality of second polymer regions based on methyl methacrylate. Insome embodiments, the first polymer regions based on urethanedimethacrylate include about 60%-99% (w/w) of the copolymer and thesecond polymer regions based on methyl methacrylate include about 1%-40%(w/w) of the copolymer. In some embodiments, the first polymer regionsbased on urethane dimethacrylate includes about 60%-80% (w/w) of thecopolymer and the second polymer regions based on methyl methacrylateincludes from about 20%-40% (w/w) of the copolymer. In some embodiments,the first polymer regions based on urethane dimethacrylate include softsegments based on poly(tetramethyl) glycol, the soft segments having amolecular weight between about 100 Da and about 5000 Da.

In some embodiments, the urethane dimethacrylate-methyl methacrylatecopolymer defines a compressive modulus between about 30 MPa and about2000 MPa. In some embodiments, the urethane dimethacrylate-methylmethacrylate copolymer defines a tensile modulus between about 30 MPaand 2000 MPa. In some embodiments, the urethane dimethacrylate-methylmethacrylate copolymer defines a failure strain between about 25% and200%.

In some embodiments, the composition further includes a radiopaquematerial.

Another aspect of the invention provides a composition of matterincluding from about 60% (w/w) to about 99% (w/w) urethanedimethacrylate monomer; from about 1% (w/w) to about 40% (w/w) methylmethacrylate monomer; an initiator; an accelerator; and an inhibitor.

In some embodiments, the composition includes between 0% (w/w) to about1% (w/w) initiator, between 0% (w/w) to about 1% (w/w) accelerator; andbetween 0% (w/w) to about 0.1% (w/w) inhibitor. In some embodiments, thecomposition includes from about 60% (w/w) to about 80% (w/w) urethanedimethacrylate monomer and from about 20% (w/w) to about 40% (w/w)methyl methacrylate monomer.

In some embodiments, the composition includes from about 1% (w/w) toabout 70% (w/w) poly(methyl methacrylate) powder.

In some embodiments, the composition includes a photoinitiator and/or athermal initiator (such as camphorquinone or benzoyl peroxide). In someembodiments, the accelerator includes N,N-dimethyl-p-toluidine. In someembodiments, the inhibitor includes hydroquinone.

In some embodiments, the composition includes an additive configured toprevent an infection (such as an antibiotic). In some embodiments, thecomposition includes a radiopaque material.

In some embodiments, the composition the composition defines a viscositybetween about 1 Pa·s and about 5000 Pa·s.

Another aspect of the invention provides an adhesive kit including afirst reservoir having a first mixture including at least one of aurethane dimethacrylate monomer and a methyl methacrylate monomer; atleast one of a photoinitiator and a thermal initiator; and an inhibitor;a second reservoir having a second mixture including at least one of aurethane dimethacrylate monomer and a methyl methacrylate monomer; andan accelerator; and an instruction for use; wherein at least one of thefirst reservoir and the second reservoir includes a urethanedimethacrylate monomer and at least one of the first reservoir and thesecond reservoir includes a methyl methacrylate monomer. In someembodiments, both the first reservoir and the second reservoir include aurethane dimethacrylate monomer and a methyl methacrylate monomer.

In some embodiments, the second reservoir further includes an inhibitor.

In some embodiments, the adhesive kit further includes poly(methylmethacrylate), such as, e.g., a third reservoir including a poly(methylmethacrylate) powder. In some embodiments the first mixture, the secondmixture and the poly(methyl methacrylate) define a component weight, anda weight of the poly(methyl methacrylate) powder is from about 1% toabout 70% of the component weight.

In some embodiments, the adhesive kit further includes a polystyrene. Insome embodiments, the adhesive kit further includes a photoinitiator anda thermal initiator.

In some embodiments, the first reservoir includes a first chamber in asyringe and the second reservoir includes a second chamber in thesyringe, wherein the syringe is configured to combine the first mixturewith the second mixture to create an adhesive mixture. In someembodiments, the syringe includes a nozzle connected with the syringeconfigured to dispense the adhesive mixture.

In some embodiments, the first reservoir and the second reservoir eachincludes from about 60% (w/w) to about 80% (w/w) urethane dimethacrylatemonomer. In some embodiments, the first reservoir and the secondreservoir each includes from about 20% (w/w) to about 40% (w/w) methylmethacrylate.

In some embodiments, the at least one initiator includes aphotoinitiator having between 0% (w/w) and about 1% (w/w)camphorquinone. In some embodiments, the at least one initiator includesa thermal initiator having between 0% (w/w) and about 1% (w/w) benzoylperoxide. In some embodiments, the accelerator includes between 0% (w/w)and about 1% (w/w) N,N-dimethyl-p-toluidine. In some embodiments, theinhibitor includes between 0% (w/w) and about 0.1% (w/w) hydroquinone.

In some embodiments, the adhesive kit includes an additive configured toprevent an infection, such as, e.g., an antibiotic. In some embodiments,the adhesive kit includes a radiopaque material.

In some embodiments, the first mixture defines a viscosity between about1 Pa·s and 5000 Pa·s.

Another aspect of the invention provides a method of attaching anorthopedic joint implant to a joint. In some embodiments, the methodincludes the steps of placing an orthopedic joint implant in a jointspace, the orthopedic joint implant having a bearing surface and anattachment surface adapted to attach the orthopedic joint implant to ajoint surface of a joint; applying a first non-urethane-containingprecursor, a second urethane-containing precursor, and a first initiatorto the attachment surface of the orthopedic joint implant; contactingthe first precursor, the second precursor, and the first initiator withthe joint surface; and copolymerizing the first non-urethane-containingprecursor with the second urethane-containing precursor and forming anadhesive copolymer including a non-urethane-containing portion based onthe first precursor and a urethane-containing portion based on thesecond precursor to thereby attach the orthopedic joint implant to thejoint.

In some embodiments, the first precursor includes a first chemicalfunctional group, the second precursor includes a second chemicalfunctional group, and the first initiator includes a free-radicalinitiator, and the method includes first precursor includes a firstchemical functional group, the second precursor includes a secondchemical functional group, and the first initiator includes afree-radical initiator, and the step of copolymerizing includes forminga covalent bond between the first functional group and the secondfunctional group in response to the free-radical initiator. In someembodiments, the first precursor includes a first ethylenicallyunsaturated group and the second precursor includes a secondethylenically unsaturated group and the step of copolymerizing includesforming a covalent bond between the first ethylenically unsaturatedgroup and the second ethylenically unsaturated group in response to afree-radical initiator. In some embodiments, the first precursorincludes first precursor molecules each having an acrylic group, and thestep of copolymerizing includes covalently bonding a plurality of firstprecursor molecules through the acrylic groups. In some embodiments, thesecond precursor includes second precursor molecules having two acrylicgroups, and the step of copolymerizing includes covalently bonding aplurality of second precursor molecules through the acrylic groups.

In some embodiments, the copolymer includes a plurality of firststructural units corresponding to the first non-urethane-containingprecursor and a plurality of second structural units corresponding tothe second urethane-containing precursor, the method further includes atleast one of forming a crosslink between at least two of the firststructural units, forming a crosslink between at least two of the secondstructural units, and forming a crosslink between a first structuralunit and a second structural unit.

In some embodiments, the first precursor includes a methyl methacrylatemonomer and the second precursor includes a urethane dimethacrylatemonomer, and the step of copolymerizing includes forming a urethanedimethacrylate-methyl methacrylate copolymer. Some embodiments includethe step of mixing the first non-urethane-containing precursor, thesecond urethane-containing precursor and the first initiator prior tothe applying step.

In some embodiments, the first initiator include a photoinitiator, andthe method includes the steps projecting light on the photoinitiator toactivate the photoinitiator; and copolymerizing the firstnon-urethane-containing precursor with the second urethane-containingprecursor and forming an adhesive copolymer to thereby attach theorthopedic joint implant to the joint in response to the activatedphotoinitiator. In some embodiments, the step of copolymerizing thefirst precursor with the second precursor includes projecting light fora time period less than about 2 minutes. In some embodiments, the stepof projecting light includes projecting light discontinuously. In someembodiments, the step of projecting light includes projecting a bluelight or a UV light. In some embodiments, the orthopedic joint implantincludes a semi-transparent material, and the step of projecting lightincludes projecting light through at least a portion of thesemi-transparent material.

Some embodiments include the step of placing a thermal inhibitor in thejoint space.

In some embodiments, the first initiator includes a thermal initiator,and the method includes the step of polymerizing a portion of the firstnon-urethane-containing precursor in response to the thermal initiatorto form a non-urethane-containing oligomeric molecule. In some suchembodiments, copolymerizing includes copolymerizing thenon-urethane-containing oligomeric molecule with the second precursor inresponse to the thermal initiator.

In some embodiments, the first initiator includes a photoinitiator, andthe method includes the steps of placing a second initiator including athermal initiator in the joint space; and projecting light on thephotoinitiator to activate the photoinitiator; wherein copolymerizingincludes copolymerizing a first portion of the firstnon-urethane-containing precursor with a first portion of the secondurethane-containing precursor in response to the activatedphotoinitiator and copolymerizing a second portion of the firstnon-urethane-containing precursor with a second portion of the secondurethane-containing precursor in response to the thermal initiator;thereby forming an adhesive copolymer including anon-urethane-containing portion based on the first precursor and aurethane-containing portion based on the second precursor.

In some embodiments, the method includes the step of placing a reactionaccelerator in the joint space.

In some embodiments, the method includes priming the attachment surfaceof the implant with an organic solution, such as, e.g., acetone, priorto the contacting step.

In some embodiments, the method includes the step of swelling theorthopedic joint implant with a solvent prior to the applying step. Insome embodiments, the method includes the step of forming an IPN orsemi-IPN between the adhesive copolymer and the orthopedic jointimplant.

In some embodiments, the method includes the step of removing abiological material from the joint prior to the contacting step.

In some embodiments, the method includes the step of interdigitating theadhesive copolymer in at least one of a feature, such as, e.g., at leastone of a bump, a depression, a groove, a pore, and a space, on theattachment surface of the orthopedic joint implant and a feature on thejoint surface. In some embodiments, the method includes the step ofinterdigitating the adhesive copolymer with cancellous bone.

In some embodiments, the attachment surface of the orthopedic jointimplant includes a polyurethane IPN or polyurethane semi-IPN, the methodincludes the step of forming a non-covalent interaction, such as, e.g.,least one of an absorption interaction, a crystallite formation, anentanglement, a hydrogen bond, a hydrophobic interaction, an ionicinteraction, a pi-bond stacking, and a van der Waals interaction,between the adhesive copolymer and the polyurethane IPN or polyurethanesemi-IPN. In some embodiments, the orthopedic joint implant includes awater-swellable IPN or a water-swellable semi-IPN, the method furtherincludes interpenetrating a portion of the adhesive copolymer with thewater-swellable IPN or water-swellable semi-IPN.

In some embodiments, the orthopedic joint implant includes an IPN orsemi-IPN having a first phase domain, the method further includes thestep of choosing a second precursor having a second phase domainconfigured to interfacially adhere to the first phase domain. In somesuch embodiments, the method includes the step forming a chemical bond,such as e.g. between the first phase domain and the second phase domain.

In some embodiments, the orthopedic joint implant includes an IPN orsemi-IPN based on a polyether urethane having a hard segment based onmethylene diphenyl diisocyanate, the method further includes the step ofchoosing a second precursor having a hard segment based on methylenediphenyl diisocyanate. In some embodiments, the orthopedic joint implantincludes an IPN or semi-IPN based on a polyether urethane having a softsegment based on poly(tetramethyl) glycol, the method further includesthe step of choosing a second precursor including a soft segment basedon poly(tetramethyl) glycol.

Another aspect of the invention provides a method of attaching a firstportion of a bone to a second portion of a bone. In some embodiments,the method includes the steps of applying a first non-urethanecontaining precursor, a second urethane-containing precursor, and afirst initiator to the attachment surface of the orthopedic jointimplant; and copolymerizing the first non-urethane-containing precursorwith the second urethane-containing precursor and forming an adhesivecopolymer to thereby attach the first portion of the bone to the secondportion of the bone. In some embodiments, the step of forming anadhesive includes forming a biodegradable adhesive. In some embodiments,the step of applying a second urethane-containing precursor includesapplying a precursor based on a lysine diisocyanate.

For purposes of this application, an “interpenetrating polymer network”or “IPN” is a material comprising two or more polymer networks which areat least partially interlaced on a molecular scale, but not covalentlybonded to each other, and cannot be separated unless chemical bonds arebroken. A “semi-interpenetrating polymer network” or “semi-IPN” is amaterial comprising one or more polymer networks and one or more linearor branched polymers characterized by the entanglement on a molecularscale of at least one of the networks by at least some of the linear orbranched macromolecules. As distinguished from an IPN, a semi-IPN is apolymer composite in which at least one of the component polymernetworks is not chemically crosslinked by covalent bonds. A “polymer” isa substance comprising macromolecules, including homopolymers (a polymerderived one species of monomer) and copolymers (a polymer derived frommore than one species of monomer or macromonomer, in which the monomersand/or macromonomers are covalently linked to each other). “Phaseseparation” is defined as the conversion of a single-phase system into amulti-phase system, an example being the separation of two immiscibleblocks of a block co-polymer into two phases, with the possibility of asmall interphase in which a small degree of mixing occurs. A “urethane”is an ester of an N-substituted carbamic acid with the structure—RNHC(═O)OR′—, where R and R′ are portions of a polymer chain joined bythe “urethane linkage” which has the structure —NC(═O)O. A“polyurethane” is a material that contains multiple urethane linkages inits backbone. An “acrylic” functional group is a carbon-carbon doublebond and a carbon-oxygen double bond, separated by a carbon-carbonsingle bond, with the carbon-carbon double bond rendering the group“ethylenically unsaturated”. A “precursor” is a molecule which canundergo polymerization thereby contributing constitutional units to theessential structure of a polymer or copolymer.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe claims that follow. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1 shows an orthopedic implant being attached to a surface of ajoint according to one aspect of the invention.

FIGS. 2A-2B schematically illustrate the formation of an adhesivecopolymer according to one aspect of the invention.

FIGS. 3A-3C show another view of an orthopedic implant being attached toa surface of a joint.

FIG. 4 shows the structure of an adhesive copolymer made according toone aspect of the invention.

FIG. 5A shows an example of a chemical precursor that may be used toform an adhesive copolymer. FIGS. 5B, 5C, and 5D show structures ofchemicals that may be used to form a precursor such as the one shown inFIG. 5A.

FIG. 6A shows components of existing dental and orthopedic products.FIG. 6B shows components of an adhesive according to one aspect of theinvention.

FIG. 7 shows interactions between a polyurethane-based adhesive polymerand a polyurethane material.

FIGS. 8A-8B shows a biodegradable adhesive copolymer being used to set abone according to one aspect of the invention. FIG. 8C shows the boneafter the adhesive copolymer has biodegraded.

FIGS. 9A-9B show an embodiment of a two part adhesive kit that can beused to make an adhesive copolymer according to one aspect of theinvention.

FIG. 10 shows an embodiment of a two part adhesive according to oneaspect of the invention.

FIG. 11 shows the composition of an adhesive mixture afterpolymerization to form an adhesive copolymer according to one embodimentof the invention.

FIGS. 12 and 13 show tensile properties of different compositions ofadhesive copolymers made according to some embodiments of the invention.

FIG. 14 shows shear strength results of adhesive copolymers such asthose used in FIGS. 12 and 13 adhered to a polyurethane.

FIG. 15 shows shear strength of adhesive copolymers such as those usedin FIGS. 12-14 adhered to a bone.

FIG. 16 shows the curing times for adhesive copolymers made according tosome embodiments of the invention compared with curing times for PMMAbone cements.

FIG. 17 shows FTIR curing processes for adhesive copolymers made usingthermal curing according to some embodiments of the invention.

FIG. 18A shows the chemical conversion occurring during the curingprocesses for adhesive copolymers made using thermal curing according tosome embodiments of the invention.

FIG. 18B shows curing processes for adhesive copolymers made using bluelight curing according to some embodiments of the invention.

FIG. 19A shows amounts of carbon and nitrogen leaching from adhesivecopolymers made according to one embodiment of the invention.

FIG. 19B shows amounts of MMA monomer released from adhesive copolymersmade according to one embodiment of the invention.

FIG. 20 shows amounts of carbon leachables from adhesive copolymers madeaccording to some embodiments of the invention.

FIG. 21 shows the stability results from accelerated biostabilitytesting of adhesive copolymers made according to some embodiments of theinvention.

FIG. 22 shows a summary of mechanical properties of an adhesivecopolymer.

FIG. 23A shows a testing device. FIG. 23B shows the results of truestress-true strain tensile testing of an adhesive copolymer using atesting device shown schematically in FIG. 23A.

FIG. 24A shows a testing device. FIG. 24B shows the results ofcompressive testing of an adhesive copolymer using a testing deviceshown schematically in FIG. 24A.

FIG. 25A shows a testing device. FIG. 25B shows the results ofcompressive creep testing of an adhesive copolymer using a testingdevice shown schematically in FIG. 25B.

FIGS. 26A-26B show a schematic of a fixture setup for performing a peeltest.

FIG. 27B shows the results of peel testing of an adhesive copolymerusing a testing device shown schematically in FIG. 27A.

FIG. 28 shows a schematic of a lap shear test device.

FIG. 29 shows a viscosity profile over time of an adhesive copolymermade according to one embodiment of the invention.

FIG. 30 shows the elastic modulus of adhesive copolymers made withdifferent amounts of MMA monomers according to some embodiments of theinvention.

FIG. 31 shows the hardness of adhesive copolymers made with differentamounts of MMA monomers according to some embodiments of the invention.

FIG. 32 shows creep recovery of adhesive copolymers made with differentamounts of MMA monomer according to some embodiments of the invention.

FIG. 33A shows peel initiation strength of adhesive copolymers made withdifferent amounts of MMA monomer on a polyether urethane according tosome embodiments of the invention. FIG. 33B shows peel propagationstrength of adhesive copolymers made with different amount of MMAmonomer on a polyether urethane according to some embodiments of theinvention.

FIG. 34A shows peel initiation strength of adhesive copolymers made withdifferent amounts of MMA monomer on an IPN or semi-IPN implant deviceaccording to some embodiments of the invention. FIG. 34B shows peelpropagation strength of adhesive copolymers made with different amountof MMA monomer on an IPN or semi-IPN implant device according to someembodiments of the invention.

FIG. 35 shows another set of results for viscosities of adhesivecopolymers made with different amounts of MMA monomers according to someembodiments of the invention.

FIG. 36 shows a comparison of peel propagation strength for adhesivecopolymers on smooth and roughened polyether urethanes.

FIG. 37 shows peel strength for adhesive copolymers adhered to polyetherurethanes after various surface treatments.

FIG. 38 shows a comparison of peel strength for adhesive copolymersadhered to polyether urethanes with and without surface acetone priming.

FIG. 39 shows peel strength for adhesive copolymers adhered to an IPN orsemi-IPN with different acetone application techniques.

FIG. 40 shows hardness of adhesive copolymers made with UDMA withdifferent amounts and weights of PTMO starting material.

FIG. 41 shows tensile modulus of adhesive copolymers made with UDMA withdifferent amounts of PTMO starting materials.

FIGS. 42A-42B shows another analysis of ultimate engineering strain andultimate engineering stress of adhesive copolymers made with UDMA withdifferent amounts of PTMO starting material.

FIGS. 43A-43B shows another set of results for peak peel initiationstrength and peel propagation strength respectively, of adhesivecopolymers made with UDMA with UDMA with different amounts of PTMOstarting material adhered to a polyether urethane.

FIG. 44 shows a summary of various properties of adhesive copolymersmade using different amounts of MMA monomer.

DETAILED DESCRIPTION

The present invention pertains to methods, compositions, and kits foradhering polymers and other materials to another material, and inparticular to bone or bone-like structures or surfaces. It provides athermal and/or light-curable polymeric adhesive with excellentmechanical properties. The invention addresses a need in the art foranchoring polymer materials to other material surfaces for use inmedical, commercial and industrial applications. These material surfacesmay be either artificial (i.e., other polymer, metal, or ceramiccompounds) or biologic tissues. A prime example of a biologic tissue isbone, either cortical or cancellous (porous). In particular, itaddresses the need for robust fixation of a compliant orthopedic implantto bone through an easy-to-apply, biocompatible compound. In someembodiments, the polymer is a hydrated polymer (e.g., a hydrogel). Insome embodiments, the polymeric orthopedic implant contains accessiblechemical functional groups such as amine, hydroxyl, carboxyl, orurethane groups, or combinations of functional groups. It can have ahomopolymer, copolymer, semi-interpenetrating or interpenetratingpolymer network structure. It can also have a laminated structurecomprising one or more of these, or a gradient IPN, semi-IPN, orco-polymer structure.

The invention also pertains to medical implants made with such polymersand their adhesion to bone and bone-like structures or surfaces. Somemedical implants are formed with a lubricious bearing (articulating)surface designed to replace cartilage, and an attachment surfacedesigned for fixation of the implant to bone for use in any joint in thebody. The joint may be, for example a shoulder joint, a finger joint, ahand joint, an ankle joint, a foot joint, a toe joint, a knee medialcompartment joint, a patellofemoral joint, a total knee joint, a kneemeniscus, a femoral joint, an acetabular joint, a labral joint, anelbow, an intervertebral facet, or a vertebral joint. The device can beimplanted on one side of joint forming a (hydrated) polymer-on-cartilagearticulation in the mammalian joint. The device could further have asecond mating component implanted on the opposing joint surface forminga (hydrated) polymer-on-(hydrated) polymer articulation. Alternatively,the device could further have a second mating component implanted on theopposing joint surface forming an articulation between a (hydrated)polymer on a metal or a ceramic.

Some embodiments of the polymeric adhesive provide fixation technologyoffer the advantage of a strong and secure bond to IPN or semi-IPNcontaining materials or devices. This enables a number of cartilagereplacement applications. Conventional orthopaedic PMMA bone cement actsas a grout and relies on interdigitation with features on an implant(such as grooves), rather than actual adhesion, to secure the implant tobone. In some embodiments, the polymeric adhesive not onlyinterdigitates with cancellous bone in the way that conventional PMMAbone cements do, it also provides direct adhesion to the anchoringsurface of IPN or semi-IPN containing materials or devices.

FIG. 1 illustrates one embodiment of the invention. Medical implant 2having a lubricious, hydrated articulation surface 10 and a stiff,attachment side 8 is fixed to bone 30 by means of an adhesive polymer 24that acts as an intermediary between bone 30 and the attachment surface6 of the implant 2. In the illustrated embodiment, the adhesive polymermixture 4 is separate from the implant and can be applied to either theattachment surface 6 of the implant or to bone 30, such as using syringe12. After the implant and bone are brought together and the adhesivepolymer mixture is cured and hardened to form the adhesive polymer 24,the implant 20 is fixed to the bone. The mechanism of adhesion of theadhesive polymer 24 and the implant attachment surface 6 or the bone 30is chemical and/or physical, with the chemical adhesion including, e.g.,covalent bonds formed between reactive functional groups found on thedevice material or bone and the chemical groups in the adhesive polymerand/or a variety of non-covalent interactions such as absorption (e.g.,chemisorption, physisorption), hydrophobic interaction, crystalliteformation, hydrogen bonds, pi-bond stacking, van der Waals interactionsand physical entanglements between the device and the cured adhesivecopolymer (e.g., at the molecular level), mechanical interlocking. Insome embodiments, the physical adhesion may be the result of in-fillingor interdigitating of a bump(s), a depression(s), a groove(s), apore(s), a rough area(s), a space(s) and/or other surface features. Insome embodiments, the adhesive copolymer is interdigitated withcancellous bone. Some, all or none of the attachment surface may havefeatures. In some embodiments, the attachment surface is smooth.

In some embodiments, the attachment surface of the orthopedic jointimplant comprises one side of a gradient polyurethane (PU) IPN orgradient polyurethane (PU) semi-IPN (including a water swellablepolyurethane IPN or semi-IPN), and the method further comprises forminga non-covalent interaction between the adhesive copolymer and thepolyurethane IPN or semi-IPN.

One aspect of the invention includes a method of attaching an orthopedicjoint implant to a joint, including placing an orthopedic joint implantin a joint space, the orthopedic joint implant having a bearing surfaceand an attachment surface adapted to attach the implant to a jointsurface of a joint; applying a first, non-urethane containing precursor,a second, urethane-containing precursor, and a first initiator to theattachment surface of the implant; contacting the first precursor, thesecond precursor, and the first initiator with the joint surface; andcopolymerizing the first, non-urethane-containing precursor with thesecond, urethane-containing precursor and forming an adhesive copolymerincluding a non-urethane-containing portion based on the first precursorand a urethane-containing portion based on the second precursor and tothereby attach the orthopedic joint implant to the joint.

A first precursor portion may be mixed with one or more other precursorportions to form a copolymer. A precursor portion may be in any form,such as a gel, a liquid, a paste, a putty, or an otherwise flowablematerial. In some embodiments, a precursor portion may include a solid,such as a bead, a grain, and/or a powder. A precursor portion mayinclude, for example, one or more precursors, such as a monomer, amacromonomer, or a polymer, one or more initiators, one or moreaccelerators, one or more crosslinkers (e.g., bis-methylene-acrylamide),one or more fillers, one or more polymers one or more treatments, one ormore radiopaque agents, and/or one or more solvents.

FIGS. 2A-2B illustrate one embodiment of the invention. A first,non-urethane-containing precursor 11 is mixed with a urethane containingprecursor 13, along with an initiator (not shown) and the initiator isactivated. In response to the activated initiator, the first precursor(“A”) polymerizes with the second precursor (“B”) to thereby form acopolymer with respect to the first and the second precursors.

In some embodiments, the first precursor may polymerize with itself. Inother embodiments, the second precursor may also polymerize with itself.Thus, any type of copolymer may be formed, such as a block copolymer(AAABBBB), an alternating copolymer (ABABAB), or a statistical (random)copolymer (ABABBBA). Any number of “A” subunits (or any number of “B”subunits) may be present in each polymer region (block). Any number ofcopolymer strands may be present. A copolymer strand may start or endwith either precursor or with the same precursors. Additional precursors(e.g. “C”, “D”, etc.) may also be included. The various combinations ofA, B, C, D, etc. may form copolymers, including branch copolymers. Aprecursor may be any (e.g., a copolymer, a monomer, an oligomer, apolymer).

Referring to FIG. 2B, in some embodiments, the copolymer may becrosslinked. In some embodiments, a crosslink(s) may be formed betweentwo “A” subunits. In some embodiments, a crosslink(s) may be formedbetween two “B” subunits. In some embodiments, a crosslink may be formedbetween an “A” subunit and a “B” subunit. In some embodiments, aUDMA-based portion of a copolymer crosslinks an MMA based portion of acopolymer. Additional copolymer subunits may additionallyself-crosslink, or crosslink with any other subunit.

The first precursor has a first chemical functional group that allows itto form a covalent bond with a second precursor which has a secondchemical functional group to form a copolymer. The first precursor, aswell as the second and any additional precursors, may have one, two,three, or four or more chemical functional groups. The first, second,and any additional chemical functional groups on a precursor may be thesame or they may be different. Functional groups on different precursorsmay be the same or may be different. In some embodiments, a precursorhas a chemical functional group that may form a covalent bond inresponse to a free-radical initiator or in response to another (e.g., anionic/anionic) initiator. In some embodiments, a chemical functionalgroup may be an unsaturated group, such as an ethylenically unsaturatedgroup (e.g., a vinyl group). In some embodiments, a chemical functionalgroup may be an acrylic group and may have a carbon-carbon double bondand a carbon-oxygen double bond separated by a carbon-carbon singlebond. An “acrylic” functional group may, for example, be derived from anα,β-unsaturated carbonyl compound. A molecule containing an acrylicgroup may be decorated with additional chemical moieties. Examples ofacrylic groups that can be used in the precursors include, but are notlimited to acrylic acid, methacrylic acid, hydroxyethyl methacrylate,and methylmethacrylate. Examples of other ethylenically unsaturatedgroups that may be used in the precursors include acrylamides andmethacrylamides (such as 2-Acrylamido-2-methyl-1-propanesulfonic,(3-Acrylamidopropyl)trimethylammonium chloride,N-Acryloylamido-ethoxyethanol, 3-Acryloylamino-1-propanol,N-tert-Butylacrylamide, Diacetone acrylamide, N,N-Dimethylacrylamide,N-[3-(Dimethylamino)propyl]methacrylamide, N-Diphenylmethylacrylamide,N,N′-Hexamethylenebis(methacrylamide), N-Hydroxyethyl acrylamide,N-(Hydroxymethyl)acrylamide, N-(Isobutoxymethyl)acrylamide,N-Isopropylacrylamide, N-Isopropylmethacrylamide, Methacrylamide,N-(3-Methoxypropyl)acrylamide, N-Phenylacrylamide,N-(Triphenylmethyl)methacrylamide,N-[Tris(hydroxymethyl)methyl]acrylamide), acid acrylates (such asAcryloyl chloride, 4-Acryloylmorpholine,[2-(Acryloyloxy)ethyl]trimethylammonium chloride,2-(4-Benzoyl-3-hydroxyphenoxy)ethyl acrylate, Benzyl 2-propylacrylate,Butyl acrylate, tert-Butyl acrylate, 2-[[(Butylamino)carbonyl]oxy]ethylacrylate, tert-Butyl 2-bromoacrylate, 4-tert-Butylcyclohexyl acrylate,2-Carboxyethyl acrylate, 2-Chloroethyl acrylate, 2-(Diethylamino)ethylacrylate, Di(ethylene glycol) ethyl ether acrylate, Di(ethylene glycol)2-ethylhexyl ether acrylate, 2-(Dimethylamino)ethyl acrylate,3-(Dimethylamino)propyl acrylate, Dipentaerythritolpenta-/hexa-acrylate, Ethyl acrylate, 2-Ethylacryloyl chloride, Ethyl2-(bromomethyl)acrylate, Ethyl cis-(β-cyano)acrylate, Ethylene glycoldicyclopentenyl ether acrylate, Ethylene glycol methyl ether acrylate,Ethylene glycol phenyl ether acrylate, Ethyl 2-ethylacrylate,2-Ethylhexyl acrylate, Ethyl 2-propylacrylate, Ethyl2-(trimethylsilylmethyl)acrylate, Hexyl acrylate, 4-Hydroxybutylacrylate, 2-Hydroxyethyl acrylate, 2-Hydroxy-3-phenoxypropyl acrylate,Hydroxypropyl acrylate, Isobornyl acrylate, Isobutyl acrylate, Isodecylacrylate, Isooctyl acrylate, Lauryl acrylate, Methyl2-acetamidoacrylate, Methyl acrylate, Methyl α-bromoacrylate, Methyl2-(bromomethyl)acrylate, Methyl 3-hydroxy-2-methylenebutyrate, Methyl2-(trifluoromethyl)acrylate, Neopentyl glycol methyl ether propoxylate(2PO/OH) acrylate, Octadecyl acrylate, Pentabromobenzyl acrylate,Pentabromophenyl acrylate, Pentafluorophenyl acrylate, Poly(ethyleneglycol) methyl ether acrylate, Poly(propylene glycol) acrylate, Soybeanoil, epoxidized acrylate, 3-Sulfopropyl acrylate, Tetrahydrofurfurylacrylate, 3-(Trimethoxysilyl)propyl acrylate, 5,5-Trimethylhexylacrylate, 10-Undecenyl acrylate), acrylic acids and salts of acrylicacid (such as Acrylic acid anhydrous, 2-Bromoacrylic acid,2-(Bromomethyl)acrylic acid, 2-Ethylacrylic acid, Hafnium carboxyethylacrylate, Methacrylic acid, 2-Propylacrylic acid, Sodium acrylate,Sodium methacrylate, 2-(Trifluoromethyl)acrylic, Zinc acrylate,Zirconium acrylate, Zirconium bromonorbornanelactone carboxylatetriacrylate, and Zirconium carboxyethyl acrylate), acrylonitriles (suchas acrylonitrile, 1-Cyanovinyl acetate, and Ethyl 2-cyanoacrylate),bisphenol acrylics (such as Bisphenol A ethoxylate diacrylate, BisphenolA glycerolate dimethacrylate, Bisphenol A glycerolate (1glycerol/phenol) diacrylate, Bisphenol A dimethacrylate, and Bisphenol Fethoxylate (2 EO/phenol) diacrylate), fluorinated acrylics (such as2,2,3,3,4,4,5,5,6,6,7,7-Dodecafluoroheptyl acrylate,3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,12,12,12-Eicosafluoro-11-(trifluoromethyl)dodecylmethacrylate,3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,12-Heneicosafluorododecylacrylate,3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,12-Heneicosafluorododecylmethacrylate, 3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-Heptadecafluorodecylmethacrylate, 2,2,3,3,4,4,4-Heptafluorobutyl acrylate,2,2,3,3,4,4,4-Heptafluorobutyl methacrylate, 2,2,3,4,4,4-Hexafluorobutylacrylate, 2,2,3,4,4,4-Hexafluorobutyl methacrylate,1,1,1,3,3,3-Hexafluoroisopropyl acrylate,1,1,1,3,3,3-Hexafluoroisopropyl methacrylate,2,2,3,3,4,4,5,5-Octafluoropentyl acrylate,2,2,3,3,4,4,5,5-Octafluoropentyl methacrylate,2,2,3,3,3-Pentafluoropropyl acrylate, 2,2,3,3,3-Pentafluoropropylmethacrylate, 1H,1H,2H,2H-Perfluorodecyl acrylate,2,2,3,3-Tetrafluoropropyl methacrylate,3,3,4,4,5,5,6,6,7,7,8,8,8-Tridecafluorooctyl acrylate,2,2,2-Trifluoroethyl methacrylate,1,1,1-Trifluoro-2-(trifluoromethyl)-2-hydroxy-4-methyl-5-pentylmethacrylate, and2-[(1′,1′,1′-Trifluoro-2′-(trifluoromethyl)-2′-hydroxy)propyl]-3-norbornylmethacrylate), malemides (such as2-[8-(3-Hexyl-2,6-dioctylcyclohexyl)octyl]pyromellitic diimide oligomer,maleimide terminated,2-[8-(3-Hexyl-2,6-dioctylcyclohexyl)octyl]pyromellitic diimide oligomer,maleimide terminated, N,N′-(o-Phenylene)dimaleimide,N,N′-(1,3-Phenylene)dimaleimide, and N,N′-(1,4-Phenylene)dimaleimide),methacrylates (such as Allyl methacrylate, 2-Aminoethyl methacrylate,2-[3-(2H-Benzotriazol-2-yl)-4-hydroxyphenyl]ethyl methacrylate, Benzylmethacrylate,Bis(2-methacryloyl)oxyethyldisulfide,2-(2-Bromoisobutyryloxy)ethylmethacrylate,2-(tert-Butylamino)ethyl methacrylate,Butylmethacrylate,tert-Butyl methacrylate, 9H-Carbazole-9-ethylmethacrylate,3-Chloro-2-hydroxypropyl methacrylate,Cyclohexylmethacrylate,2-(Diethylamino)ethyl methacrylate, Di(ethylene glycol)methyl ether methacrylate,2-(Diisopropylamino)ethylmethacrylate,2-(Dimethylamino)ethyl methacrylate,2-Ethoxyethylmethacrylate,Ethylene glycol dicyclopentenyl ether methacrylate,Ethylene glycol methyl ether methacrylate,Ethylene glycol phenyl ethermethacrylate,2-Ethylhexyl methacrylate, Ethylmethacrylate,Ferrocenylmethyl methacrylate, Furfuryl methacrylate,Glycidyl methacrylate,Glycidyl methacrylate, Glycosyloxyethylmethacrylate, Hexyl methacrylate,Hydroxybutylmethacrylate,2-Hydroxyethyl methacrylate,2-Hydroxyethylmethacrylate,Hydroxypropyl methacrylate,2-Hydroxypropyl2-(methacryloyloxy)ethyl phthalate, Isobornyl methacrylate,Isobutylmethacrylate, 2-Isocyanatoethyl methacrylate,Isodecyl methacrylate,Lauryl methacrylate,Methacrylic acid N-hydroxysuccinimide ester,[3-(Methacryloylamino)propyl]dimethyl(3-sulfopropyl)ammonium hydroxide,[3-(Methacryloylamino)propyl]trimethylammonium chloride, Methacryloylchloride purum, Methacryloyl chloride,[2-(Methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide,2-Methacryloyloxyethyl phosphorylcholine,[2-(Methacryloyloxy)ethyl]trimethylammonium chloride,[2-(Methacryloyloxy)ethyl]trimethylammonium methyl sulfate,2-(Methylthio)ethyl methacrylate, mono-2-(Methacryloyloxy)ethyl maleate,mono-2-(Methacryloyloxy)ethyl succinate, 2-N-Morpholinoethylmethacrylate, 1-Naphthyl methacrylate, Pentabromophenyl methacrylate,Pentafluorophenyl methacrylate,Phenyl methacrylate, Phosphoric acid2-hydroxyethyl methacrylate ester, Poly(ethylene glycol) behenyl ethermethacrylate, Poly(ethylene glycol) 2,4,6-tris(1-phenylethyl)phenylether methacrylate, Poly(propylene glycol) methacrylate, Propylmethacrylate, 1-Pyrenemethyl methacrylate, Solketal methacrylate,Stearyl methacrylate, 3-Sulfopropyl methacrylate, TEMPO methacrylate,Tetrahydrofurfuryl methacrylate, 2,4,6-Tribromophenyl methacrylate,3-(Trichlorosilyl)propyl methacrylate, Triethylene glycol methyl ethermethacrylate,1,1,1-Trifluoro-2-(trifluoromethyl)-2-hydroxy-4-methyl-5-pentylmethacrylate,2-[(1′,1′,1′-Trifluoro-2′-(trifluoromethyl)-2′-hydroxy)propyl]-3-norbornylmethacrylate, 3-(Trimethoxysilyl)propyl methacrylate,3,3,5-Trimethylcyclohexyl methacrylate, (Trimethylsilyl)methacrylate,2-(Trimethylsilyloxy)ethyl methacrylate,3-[Tris(trimethylsiloxy)silyl]propyl methacrylate, and Vinylmethacrylate), and polyfunctional acrylics (such as Acrylamide:N,N′-Methylenebisacrylamide, 3-(Acryloyloxy)-2-hydroxypropylmethacrylate, Bis[2-(methacryloyloxy)ethyl] phosphate, Bisphenol Apropoxylate diacrylate, 1,3-Butanediol diacrylate, 1,4-Butanediol,1,3-Butanediol dimethacrylate,1,4Butanedioldimethacrylate,N,N′(1,2Dihydroxyethylene)bisacrylamide,Di(trimethylolpropane) tetraacrylate, Diurethane dimethacrylate,N,N′-Ethylenebis(acrylamide), Glycerol 1,3-diglycerolate diacrylate,Glycerol dimethacrylate, Glycerol propoxylate 1,6-Hexanediol diacrylate,1,6-Hexanediol dimethacrylate, 1,6-Hexanediol ethoxylate diacrylate,Hydroxypivalyl hydroxypivalate bis[6-(acryloyloxy)hexanoate], Neopentylglycol diacrylate, Neopentyl glycol propoxylate, Pentaerythritoldiacrylate monostearate, Pentaerythritol tetraacrylate, Pentaerythritoltriacrylate, Poly(propylene glycol) diacrylate, Poly(propylene glycol)dimethacrylate,1,3,5-Triacryloylhexahydro-1,3,5-triazine,Tricyclo[5.2.1.02,6]decanedimethanol diacrylate, Trimethylolpropaneethoxylate,Trimethylolpropane ethoxylate triacrylate, Trimethylolpropaneethoxylate triacrylate, Trimethylolpropane ethoxylate triacrylate,Trimethylolpropane propoxylate triacrylate, Trimethylolpropanetriacrylate, Trimethylolpropane trimethacrylate, Tri(propylene glycol)diacrylate, and Tris[2-(acryloyloxy)ethyl] isocyanurate and salts andvariations thereof. In some embodiments, urethane dimethyacrylate isused.

A precursor (e.g., with a chemical, functional group) may have anystructure or any additional functional groups. In one embodiment, thefirst precursor is a monomer comprising an ethylenically unsaturatedgroup and the second precursor is a macromonomer or oligomer containingethylenically unsaturated end groups. In another embodiment, the firstprecursor is a monomer comprising an acrylic group and the secondprecursor is a macromonomer or oligomer containing acrylic end groups.

In some embodiments, a precursor may contain or may be capable offorming (e.g., with another precursor) a bond or interaction with asurface to which it may be attached. A precursor may be chosen tocontain one or more subunits that are the same or similar to portions ofa surface (e.g., subunits on a surface). A method may include choosingan adhesive precursor having a segment (e.g., a soft segment/phase suchas based on PTMO, or a hard segment/phase such as based on MDI) that isbased on the same material (segment or phase) present on an attachmentsurface. In some embodiments, segments from the adhesive copolymer mayinterfacially adhere with segments in the adhesive copolymer, such as bychemical bonds (e.g. hydrogen bonds) or any of the interactionsdescribed above. FIG. 7 shows hydrogen bonding (dashed lines) betweenElasthane™ 75D (top) and the urethane portion of a methacrylate-cappedpolyurethane (e.g., UDMA) of a polymeric adhesive (bottom). The bondingmay occur, for example, in the presence of a partial solvent, such asMMA. In one embodiment, the polymeric adhesive employs similar chemistryto Elasthane™ 75D, which comprises hard and soft urethane segments. Inthis embodiment, the polymeric adhesive was designed based on thechemical structure of Elasthane™ so that hydrogen bonding betweenurethane bonds of Elasthane™ and the polymeric adhesive was promoted tohelp achieve desired adhesion. It is speculated that the same type ofhydrogen bonding that occurs between polyurethane (Elasthane™) chains,also occurs between Elasthane™ and the polymeric adhesive, and inparticular for example, when the lengths and varieties of the hard andthe soft segments have been chosen to be similar. The presence of MMAmay also be important as it acts as a partial solvent for Elasthane™ anddiffuses into it. While not wanting to be bound by any particulartheory, it is hypothesized that this provides mobility to the Elasthane™hard segments during curing, allowing more hydrogen bonds to form withthe hard segments contained in the polymeric adhesive. MMA also improveswettability characteristics of the polymeric adhesive. In addition, itis speculated that MMA (or another precursor or another solvent) maypartially penetrate a polyurethane or polyurethane-based hydrogel orother polymer and by polymerizing in situ, form hoops or loops or otherentanglements with a polyurethane chain, a hydrogel chain, or anotherpolymer chain. FIG. 7 depicts the hypothesized adhesive mechanism. Insome embodiments, a segment of an adhesive precursor or adhesivecopolymer has the same basic composition as a segment of an attachmentsurface to which the adhesive precursor is attached (or is prepared forattachment). In some embodiments, the overall length of an adhesiveprecursor (hard or soft) segment may be the same, similar, or may bedifferent from the overall length of an attachment surface (hard orsoft) segment. In some embodiments, an overall chain length between ahydrogen-bonding area of an adhesive precursor may be similar to theoverall length between a hydrogen-bonding area of an adhesive precursorof an attachment surface.

An adhesive copolymer for medical use (e.g. as a medical adhesive) maybe biocompatible or non-toxic or have low toxicity. In some embodiments,a precursor and/or a copolymer made from a precursor (e.g., for anon-medical use such as a non-medical adhesive, glue, or grout) may ormay not be biocompatible or be non-toxic or have low toxicity.

In some embodiments, an adhesive copolymer may be tinted or colored. Todetect polymeric adhesive that has been spilled or leaked outside (orinside) of the surgical area, some embodiments of the polymeric adhesiveare a distinctive color, such as, a color not normally found in thebody. Such coloring would make stray drops easily seen by a surgeon. Anexample of such coloring is through the use of trypan blue, which is aknown, biocompatible surgical dye.

In some embodiments, a medical implant (e.g. an orthopedic device) mayinclude a stiff backing comprising a biocompatible polyurethane IPN orpolyurethane semi-IPN having soft segments based upon a first subunitand hard segments based upon a second subunit, and a precursor for anadhesive polymer may comprise the same (or similar) first subunitsand/or second subunits.

In some embodiments, a (second) precursor may be or may be based on aurethane or polyurethane (e.g. a precursor may have one or more urethanelinkages. A urethane linkage can be formed in any way, such as, forexample, by the reaction of an isocyanate and a hydroxyl group. Aurethane is described in the art as an ester of carbamic acid (or“carbamate esters”). For the purposes of this invention, and as is oftendone so in the art, the terms “urethane” and “carbamate” (as well ascarbamate esters) are used interchangeably, such that polyurethanes arematerials including multiple urethane (carbamate) linkages. In someembodiments, a polyurethane may also contain one or more other reactionproducts of an isocyanate(s), such as a urea linkage(s) which may beformed, for example, from the reaction between an isocyanate and anamine within their backbone, in which case it is referred to as apolyurethane urea. In some embodiments, a precursor (e.g. to be usedwith the urethane based precursor to generate an adhesive copolymer) maylack a urethane linkage (e.g., may be non-urethane-containing). In someembodiments, the first precursor that is lacking a urethane linkage doesnot generate a urethane linkage upon polymerization. In other words, itdoes not yield a polymer that contains urethane linkages in itsbackbone. In some embodiments, a first precursor may generate orcontribute to the formation of a urethane linkage upon copolymerization.

In some embodiments, a first precursor comprises first precursormolecules having one acrylic group. In some embodiments, a secondprecursor comprises molecules having two acrylic groups. In someembodiments, the first precursor includes one acrylic group and nourethane linkages, and the second precursor includes two acrylic groupsand one or more urethane linkages (e.g., one, two, three, four, five, ormore than 5 urethane linkages).

FIG. 4 shows a urethane based adhesive copolymer according to one aspectof the invention. Any polyurethane or any polyether urethane basedadhesive copolymer may be used. In one embodiment, Elasthane™ may beused as a polyether urethane based adhesive copolymer. In oneembodiment, the adhesive comprises a methacrylate-capped polyetherurethane (PEU) oligomer copolymerized with MMA as shown in FIG. 4.

The urethane dimethacrylate-methyl methacrylate copolymer (e.g., a PMMAcopolymer or PMMA-urethane copolymer) shown in FIG. 4 is made bycopolymerizing a first precursor comprising a methyl methacrylatemonomer (MMA) have an acrylic functional group and a second precursorcomprising a urethane dimethacrylate monomer (UDMA), having two acrylicgroups and a urethane linkage, as shown in FIG. 5A.

Other types of polyurethane oligomers can also be used, such aspolycarbonate-based oligomers. In some embodiments, the PEU oligomer(“second precursor”) may be made by reacting methylene diphenyldiisocyanate (MDI) (FIG. 5B) and poly(tetramethylene oxide) (PTMO) (FIG.5C) in the first place and then capping the oligomer by reacting it with2-hydroxyethyl methacrylate (HEMA) (FIG. 5D) to form acrylicfunctionalized end groups (e.g. methacrylate functionalized end-groups).An initiator (e.g. a UV initiator), such as2-hydroxy-2-methylpropiophenone, may then be added, and/or a smallamount of inhibitor, such as hydroquinone, may also be added to improveshelf life.

PTMO used to make a UDMA precursor may be of any molecular weight. Insome embodiments, the PTMO may be from about 100 Da to about 5,000 Da.In some embodiments, the PTMO may be from about 400 Da to about 4000 Da,from about 400 Da to about 3000 Da, from about 400 Da to about 2000 Da,from about 400 Da to about 1200 Da, or from about 600 Da to about 1000Da. In some embodiments, the PTMO is 250 Da. In some embodiments, thePTMO is 650 Da. In some embodiments, the PTMO is about 650 Da. In someembodiments, the PTMO is about 1000 Da. In some embodiments, PTMOmolecules used to make a UDMA precursor are all the same or about thesame size. In some other embodiments, the PTMO molecules used to make aUDMA precursor are different sizes. In some embodiments, the PTMO is amixture of a first PTMO having a molecular weight about 650 Da andsecond PTMO have a molecular weight about 1000 Da. In embodiments inwhich more than one size of PTMO is used, any % ratio can be used. Anysize of PTMO can be more than 10%, more than 20%, more than 30%, morethan 40%, more than 50% of a mixture. In other embodiments, two or morespecies of UDMA may be made separately, and combined after manufacture.

Chemically speaking, UDMA molecules can be considered methylmethacrylate-terminated polyurethane chains. A methylmethacrylate-terminated polyurethane chains can be manufactured throughan isocyanate-quenching and chain-terminating reaction to placemethacrylate groups at both ends of a polyurethane. Chemical reactionsthat may take place include the acrylic free radical polymerization ofMMA to form PMMA, polymerization of UDMA, copolymerization of MMA withUDMA, crosslinking of UDMA with PMMA, and self-crosslinking of UDMA. Oneview of the material is shown schematically in FIG. 2.

In some embodiments, UDMA alone may be polymerized to form a UDMA-basedpolymer adhesive. A UDMA-based polymer adhesive may be self-crosslinked.However, UDMA is a viscous oligomer that can be difficult to handle. Dueto its high viscosity, the UDMA alone generally has limited surfacewetting capabilities that, in turn, can limit its adhesion strength toIPN or semi-IPN containing materials. In addition, in some embodiments,a pure UDMA (post-crosslinking) polymer has a relatively low stiffness(E<100 MPa) that may be not high enough to bridge an IPN or semi-IPNcontaining material's—bone stiffness mismatch(E_(IPN/semi-IPN containing material)≈35 MPa, E_(Bone)≈500-3500 MPa).Stiffness bridging is important for some arthroplasty applications as itreduces the shear forces that are developed at the device-polymericadhesive and polymeric adhesive-bone interfaces. (In other situations,stiffness bridging and the other limitations may not be an issue and aUDMA-based polymer may be a useful adhesive). In order to improveviscosity, an additional component (e.g. a polymer or a monomer that isable to polymerize with a urethane) may be added. Different amounts of amonomer, such as methyl methacrylate (MMA) may be added to differentformulations. The more MMA, the less viscous the adhesive material isprior to curing. The viscosity of the adhesive prior to curing plays animportant role in the proper application of the material during surgicalimplantation. For instance, the adhesive should be viscous enough toflow over a surface within a reasonable amount of time, but not so runnythat it flows uncontrollably to undesired areas. Photoinitiator andinhibitor quantities can be adjusted accordingly. MMA copolymerizes withmethacrylate-capped PU to form a new copolymer (FIG. 4) comprised ofsections of PU and sections of PMMA. The final copolymer (PU PMMA)product has proven superior mechanical and adhesive properties than thePU oligomer alone in the uncured state.

UDMA (or other polyurethanes) and MMA mix very well and form acrosslinked UDMA-MMA copolymer that has good properties in terms ofadhesion strength, stiffness and creep recovery. In addition, MMA is apartial solvent for Elasthane™ polyether polyurethanes and wehypothesize that this improves adhesion. The viscosity of the polymericadhesive must also be considered so that the polymeric adhesive has goodpenetration into the cancellous bone pores (size: 200-1000 μm). FIG. 11demonstrates the final (post crosslinking) chemical composition of oneembodiment of the cured polymeric adhesive as measured using variousanalytical techniques (FTIR, GC, TOC).

In some embodiments, an additional advantage of the described polymericadhesive is low monomer release. Conventional PMMA bone cements areknown to release MMA monomer into the body due to slow and incompletepolymerization. Early experiments have shown that the polymeric adhesiveaccording to the disclosure has an initial MMA monomer release that isapproximately two times lower than that of most conventional PMMA bonecements [6], believed to be in part due to crosslinking by themethacrylate-terminated UDMA macromonomers. In agreement with this data,an initial cytotoxicity assay (ISO 10993-5) yielded a score of 0(0-nontoxic, 4-toxic) for one formulation of the described polymericadhesive [8].

Any UDMA may be used. By UDMA is meant a urethane molecule made from anyhard segment and usually two other chemicals (a soft segment, and achain extender) each typically containing at least two hydroxyl groups(diol compounds) that form the basis of a UDMA structure. The UDMA canhave any type of hard segment, soft segment, or chain extender. Anyisocyanate can be used to form the hard segment (e.g. aliphatic oraromatic). Examples of materials that may be used include but are notlimited to 1,5 napthalene diisocyanate (NDI), 2,6 tolyene diisocyanateor 2,4 toluene diisocyanate (TDI)3,3-bitoluene diisocyanate (TODI),cyclohexyl diisocyanate (CHDI), hexamethyl diisocyanate (HDI),isophorone diisocyanate (IPDI), methylene bis(p-phenyl) isocyanate,methylene diphenylisocyanate (MDI), and methylene bis (p-cyclohexylisocyanate (H12MDI) and derivatives and combinations thereof. Anymaterial can be used to form the soft segment. Examples of materialsthat can be used include but are not limited to hydrogenatedpolybutadiene. polyethylene oxide (PEO), hydroxy terminated butadiene,hydroxybutyl terminated polydimethylsiloxane (PDMS), hydroxyl terminatedpolyisobutylene, poly (1,6 hexyl 1,2 ethyl carbonate, polycaprolactone,polycarbonate, polyethylene adipate, polyhexamethylene carbonate glycol,polypropylene oxide (PPO), polytetramethylene adipate,poly(dimethylsiloxane), poly(tetramethylene oxide) (PTMO), andderivatives and combinations thereof. Any material may be used to formthe chain extender portion. Examples of materials that may be used butare not limited to 1,4 butanediol, 4, 4′methylene bis (2-chloroaniline)(MOCA), ethylene diamine, ethylene glycol, and hexane diol andderivatives and combinations thereof.

In some embodiments, copolymerization includes a first initiator, andthe first initiator comprises a photoinitiator, and the method furthercomprising projecting light on the photoinitiator to activate thephotoinitiator; and copolymerizing the first, non-urethane-containingprecursor with the second, urethane-containing precursor and forming anadhesive copolymer to thereby attach the orthopedic joint implant to thejoint in response to the activated photoinitiator. Photopolymerizationis widely and safely used in dental cement products. Any type ofphotoinitiator may be used, including, but not limited to acetophenone,benzophenone, benzoin ethyl ether, 4-benzoylbiphenyl, bisacrylphosphineoxide, 4,4′-bis(diethylamino)benzophenone, camphorquinone,2-chlorothioxanthen-9-one, 4,4′-dihydroxybenzophenone,4,4′-dimethylbenzil, ethylanthraquinone,2-hydroxy-2-methylpropiophenone, 2,2-dimethoxy-2-phenylacetophenone,methybenzoylformate, monoacrylphosphine oxide, and phenylpropanedione.In some embodiments, a photoinitiator that has previously been used inthe body such as in a bone cement or dental cement and appears to havelong term biocompatibility may be chosen.

In one embodiment, the adhesive comprises low molecular weightpolyurethane chains (25-99%), methyl methacrylate (MMA) monomer (0-75%),a polymeric photoinitiator (1-20%), and an inhibitor (1-500 ppm). Theadhesive may be applied between the two materials to be bonded together,one of which is at least semi-transparent and allows light to passthrough it.

Any amount of photoinitiator may be used that initiates (and propagates)copolymerization of the monomers. Between 0% to less than about 1%, toless than about 0.5%, to less than about 0.4%, to less than about 0.3%,to less than about 0.2%, or to less than about 0.1% photoinitiator maybe used. More or less photoinitiator may be used for any reason as longas a copolymer can be made. An amount of photoinitiator may be chosenbased on the stoichiometry of the reaction, and the amounts of the firstprecursor and second or additional precursors. For example, the amountof photoinitiator may depend on the MMA and UDMA content, since themolecular weights of MMA and UDMA are different. However, in someembodiments, a lower amount of photoinitator may be used if for example,dual (hybrid) initiation including both photoinitiation and thermal(chemical) initiation are performed. A relatively higher amount ofphotoinitiator may be used if, for example, if an orthopedic jointimplant, adhesive mixture, or other structure through which activatinglight must pass, has an opaqueness or otherwise reduces light transfer.

Light may be projected to activate the photoinitiator. Light may beprojected for any length of time to cure or polymerize the adhesiveprecursor as needed. Light may be projected for between 0 seconds toabout 10 seconds, to about 20 seconds, to about 30 seconds, to about 1minute, to about 2 minutes, to about 3 minutes, to about 4 minutes, toabout 5 minutes, to about 10 minutes. In some embodiments, light may beprojected until the adhesive mixture has substantially entirely cured(e.g. for 10 seconds, 20 seconds, 30 seconds, 1 minute, 2 minutes, 3minutes, 4 minutes, 5 minutes, or 10 minutes). In some embodiments,light may be projected continuously. In some other embodiments, lightmay be projected discontinuously, such as with one, two, three, or fouror more than four on-off cycles. Each on cycle and each off cycle may beany length. A cycle may be the same time duration as another cycle, ormay be a different time duration. A light may be projecteddiscontinuously for any reason. A light may be projecteddiscontinuously, for example, so as to start the polymerization processto increase an initial polymer mixture viscosity, allow time for implantor adhesive placement (e.g. in a joint), and then to further or completethe curing process after the implant is in place. A light may beprojected discontinuously so as to control the polymerization rate, suchas to reduce a speed of polymerization or reduce an amount of heat thatis generated. A light may be projected with variable intensity so as tocontrol a polymerization rate, such as to reduce a speed ofpolymerization or reduce an amount of heat generated. In someembodiments, intensity may start high and taper down, to, for example,reduce the polymerization rate and the amount of heat generated. In someembodiments, a high intensity burst may follow to ensure that conversionis sufficiently completed. In some embodiments, a temperature may bemonitored (during polymerization), e.g., by infrared or contactthermometer. In some embodiments, an intensity of light can be adjusted,such as by a temperature-intensity feedback loop, so that thetemperature does not exceed a physiologically relevant limit.

A light may be projected at any wavelength(s) that activates thephotoinitiator. A projecting light may project ultraviolet light (UV),visible light, or infrared light. In some embodiments projecting lightmay comprise projecting UV light. In some embodiments projecting lightmay project blue light (e.g. between 400 nm and 500 nm; from 400 nm-420nm, from 420 nm-440 nm, from 440 nm-460 nm, from 460 nm-480 nm, and/orfrom 480 nm-500 nm). In some embodiments, camphorquinone 1% w/w may beused as a photoinitiator in combination with an LED light source at 450nm for photoinitiation. In some embodiments, the orthopedic jointimplant comprises a semi-transparent material, and treating comprisesprojecting light through at least a portion of the semi-transparentmaterial.

According to some embodiments, a method of copolymerizing an adhesivemixture includes copolymerizing the mixture in response to supplying athermal or chemical initiator. Any thermal or chemical initiator may beused. In some embodiments, a thermal or chemical initiator is activatedat the time it contacts an adhesive mixture. In some other embodiments,a thermal or chemical initiator may be activated by an electrical chargeor elevated temperature. In other embodiments, a lower temperature mayaid initiation. In other embodiments, an initiator may be present in amixture, but may be prevented from activation by the action of aninhibitor.

In some embodiments, an adhesive mixture includes both a photoinitiatorand a thermal initiator, or both initiators are applied along with anadhesive mixture (such as on a joint surface), and a method ofcopolymerizing an adhesive mixture includes copolymerizing the adhesivemixture in response to both an activated photoinitiator and a thermalinitiator. Any one or more photoinitiators can be used at any step.Photoinitiators and chemical initiators may be chosen based on theirsolubility(ies) with the precursor solutions or other precursormaterials. Initiators include, but are not limited to2-hydroxy-2-methyl-propiophenone and 2-hydroxy-1-[4-(2-hydroxyethoxy)phenyl]-2-methyl-1-propanone, 2-oxoglutaric acid,azobisisobutyronitrile, benzoyl peroxide, camphorquinone, potassiumpersulfate, and sodium persulfate).

The composition and components for some embodiments of an adhesiveprecursor mixture, may include one or more of a first precursor (MMA), asecond precursor (UDMA), a photoinitiator (camphorquinone), a thermalinitiator (benzoyl peroxide), an accelerator (N,N-dimethyl-p-toludine),and an inhibitor (hydroquinone). The adhesive precursor mixture may becured by photoinitiation and/or thermal initiation.

Long term biocompatibility is important for some embodiments of anadhesive copolymer, such as for use in the body in a joint implant.Although needing to perform very different functions, such as acidetching of tooth enamel and dentin, tolerating various forms of wear andabrasion after curing, matching thermal expansion of the tooth due totemperature changes, and maintaining an unchanging, aestheticallypleasing tooth color, use of certain materials in composite dentalrestoratives suggests they possess a long term biocompatibility thatsuggests they may be good choices for use in an adhesive copolymer, suchas for attaching a orthopedic joint replacement to a joint surface.

Similarly, although existing bone cements have many limitations,especially for the purposes described herein, use of their componentsthat appear to have shown long term biocompatibility or long termtolerance may be worthwhile. MMA, for example, has long been a componentused in various bone cements.

FIGS. 6A-B show commercial products (dental adhesive cements, dentalcavity liner, and orthopedic bone cement) that also contain constituentsof an adhesive mixture made according to one aspect of the invention andthat may have long term biocompatibility. In some embodiments, aninhibitor and/or accelerator may be added to a precursor mixture, inpart, because it appears to have long term biocompatibility.

Two (or more) types of initiators may be applied for any reason thatimproves the polymerization reaction. A first initiator may control aviscosity of the material, may allow only partial curing to take place,or may allow only a portion of adhesive to attach. For example, use of afirst photoinitiator may render an adhesive mixture more viscous andeasier to handle. Use of a first photoinitiator may allow a user toplace an implant in a preferred position, and to quickly cure theimplant in the preferred position. The reaction may be very fast (lessthan 10 seconds, less than 20 seconds, less than 30 seconds, less than aminute, less than 2 minutes, or less than 3 minutes. Selective use of afirst initiator may allow an implant to be put into position (such as ona joint surface) and attached to the surface, while a second initiatormay attach the implant to a second surface (such as an attachmentsurface).

Using two types of initiators may increase the amount of monomerpolymerized and thereby reduce undesired monomer release from theadhesive polymer (e.g., into a body of a patient). Using a second methodof curing (e.g., thermal) after a first method of curing (e.g.,photoinitiation) may allow areas of the adhesive mixture that are notsufficiently penetrated by a light source to be photocured to polymerizein response to thermal initiation.

One aspect of the invention provides a composition of matter comprisinga urethane dimethacrylate-methyl methacrylate copolymer comprising aplurality of first polymer regions based on urethane dimethacrylatealternating with a plurality of second polymer regions based on methylmethacrylate to thereby form the urethane dimethacrylate-methylmethacrylate copolymer. In some embodiments, the urethane regions (theurethane dimethacrylate regions or modified urethane dimethacrylateregions) comprise about 60% (w/w) to about 80% (w/w), about 60% (w/w) toabout 90% (w/w), about 60% (w/w) to about 99% (w/w), or about 70% (w/w)to about 90% (w/w) of the adhesive copolymer. In some embodiments, themethyl methacrylate regions comprise from about 20% (w/w) to about 40%(w/w), from about 1% to about 20% (w/w), or from about 1% (w/w) to about40% (w/w). In some embodiments, the UDMA regions include soft segmentsbased on PTMO, and the soft segments have a molecular weight betweenabout 100 Da and about 5000 Da. In some embodiments, the UDMA-MMAcopolymer defines a compressive modulus between about 30 MPa and about2000 Mpa. In some embodiments, the UDMA-MMA copolymer defines a tensilemodulus between about 30 MPa and about 2000 Mpa. In some embodiments,the UDMA-MMA copolymer defines a failure strain between about 25% and200%. As well as providing other advantages, such as excellent fixationcapabilities and mechanical strength, UDMA combined with PMMA reducesthe brittleness otherwise found in pure PMMA.

An accelerator may accelerate the decomposition of an initiator, forexample to generate a free radical. Any type of accelerator(s) may beused, including but not limited to N,N-dimethyl-p-toluidine,N,N-dimethylaniline, N,N-dimethylaminobenzyl alcohol,N,N-dimethylaminobenzyl methacrylate, 2-(Dimethylamino)ethylmethacrylate, ethyl 4-(dimethylamino)benzoate, and3,4-methylenedioxybenzene methoxyl methacrylate.

In some embodiments, a method of attaching an orthopedic joint implantto a joint includes the step of priming the attachment surface of theimplant prior to contacting the surface of the implant with adhesiveprecursors. Priming the surface may include priming the surface with anorganic solvent (e.g., acetone).

In some embodiments, a method of attaching an adhesive copolymer to amedical implant includes the step of swelling the implant with a solventprior to applying the precursors to the implant. In some embodiments, atleast a portion of the implant comprises a polyurethane, and any solventthat swells the polyurethane, but does not dissolve it may be used. Thesolvent is chosen based on the specific qualities and phases of thepolymers and monomers. For instance, acetic acid is capable of swelling,but does not dissolve many polyurethanes. Other solvents that can beused include, but are not limited to, acetone, butanol (or any alkylalcohol), dichloromethane, dimethylacetamide, diethylether,dimethylformamide, dimethylsulfoxide, methanol, propanol,tetrahydrofuran or combinations of these. Taking into account thesolubilities in the phases of the polymer, solvents with varying degreesof swelling can be chosen. Solubilities of the solvents and componentsof the material to be swollen can be obtained from polymer textbookssuch as The Polymer Handbook or can be measured experimentally. In someembodiments, an IPN or semi-IPN is formed between the adhesive copolymerand the orthropedic joint implant, such as after partially swelling theorthopedic joint implant with a solvent.

One aspect of the invention provides a method of attaching a firstportion of a bone to a second portion of a bone, including the steps ofapplying a first, non-urethane-containing precursor, a second,urethane-containing precursor, and a first initiator to the attachmentsurface of the orthopedic joint implant; and copolymerizing the firstprecursor with the second precursor and forming an adhesive copolymer tothereby attach the first portion of the bone to the second portion ofthe bone. FIGS. 8A-C illustrate use of an adhesive copolymer to help seta bone. Patient 40 has a break in bone 42, exposing bone surface 44. Abiodegradable adhesive precursor mixture 48 is premixed in syringe 46and applied to the surface. In FIG. 8B, bone 52 of patient 50 is set bya layer of cured adhesive 58 after syringe 56 is removed. In FIG. 8C,the biodegraded adhesive has biodegraded and the new bone tissue 66 hasgrown into the region of the previous break to mend the break. Abiodegradable adhesive may be based on, for example, a secondurethane-containing precursor based on a lysine diisocyanate segment. Abiodegradable adhesive may be degraded by, for example, contact withoxygen and/or with a body fluid such as, for example, blood,interstitial fluid, saliva, or urine.

One aspect of the invention provides a composition of matter includingbetween 60% to 99% (e.g. 60% to 80%) urethane dimethacrylate monomer,between 1% to 40% (e.g. 20% to 40%) methyl methacrylate monomer, between0% to 1% (w/w) initiator (e.g. a photoinitiator, a thermal initiator),between 0% and 1% accelerator; and between 0% to 0.01% inhibitor.composite adhesive combines the desirable ductility of polyurethane withthe stiffness and strength of PMMA bone cement.

The relative concentrations of polyurethane chains and MMA monomer canbe varied to alter the physical, mechanical and chemical properties ofthe adhesive. The composition may further include from 1% to 70%poly(methyl methacrylate powder). PMMA may provide useful propertieswhile reducing the relative amount of unreacted monomer. In someembodiments, the initiator is camphorquinone or benzoyl peroxide. Insome embodiments, the accelerator is hydroquinone. Any additionalcomponents mentioned herein may be added, such as an antibiotic orradiopaque material. Barium sulfate and iohexol (an iodine contrastagent) may be added to the adhesive to increase its radioopacity. Insome embodiments, the composition defines a viscosity between about 1Pa·s and about 5000 Pa·s.

At their contact interface, a polyurethane-based implant will formmolecular entanglements and both physical and chemical bonds with thepolyurethane-based adhesive, in spite of the fact that the device is apolyurethane-PAA composite and the adhesive is comprised of apolyurethane-MMA composite. Bonding is facilitated in particular by thecommon polyurethane component in both materials. For example, a gradientIPN or semi-IPN of PU and PAA will feature one side with a preponderanceof PU relative to PAA, and this side would bond well with the UDMA-MMAcomposite adhesive. The invention provides a unique combination ofpolyurethane polymer chains and an MMA monomer in a UV-curable adhesivethat has sufficient mechanical properties for orthopaedic, medical,commercial, and industrial applications that have high mechanicaldemands.

One aspect of the invention provides a kit or packaged components. Thekit may be used to make an adhesive copolymer. A kit may contain thecomponents in any combination that do not copolymerize before mixing,and that would, upon mixing, form an adhesive copolymer as describedherein. In some embodiments, the components are packaged in two parts,Part A and Part B, that can be mixed together prior to use.

A kit may include a first reservoir comprising a first mixture includingat least one of a urethane dimethacryate monomer and a methylmethacrylate monomer, at least one of a photoinitiator and a chemicalinitiator; and an inhibitor; a second reservoir comprising a secondmixture comprising: at least one of a urethane dimethacrylate monomerand a methyl methacrylate monomer; an accelerator; wherein at least thefirst reservoir or the second reservoir comprises a urethanedimethacrylate monomer and at least the first reservoir or the secondreservoir comprises a methyl methacrylate; and an instruction for use.

In some embodiments, both the first and the second reservoirs comprise aurethane dimethacrylate monomer and a methyl methacrylate monomer. Insome embodiments, the second reservoir comprises an inhibitor. In someembodiments, the kit further includes poly(methyl methacrylate), such asa PMMA powder. The PMMA powder may be, for example from about 1% toabout 70%, about 10% to about 60%, about 20% to about 50%, or about 30%to about 40% of the total weight of the components (the combined weightof the components of the first reservoir, the components of the secondreservoir, and the PMMA). The poly(methyl methacrylate) may be any formand may be in one of the above mentioned reservoirs, or may be in athird reservoir. The PMMA (or the other components) may be in the formof a gel, a liquid, a powder, a putty, or a solid.

In some embodiments, a kit may include one or more additionalcomponents, such as an accelerator, an additive configured to prevent aninfection (e.g., an anti-fungal treatment or an antibiotic), a filler,one or more initiators, a radiopaque material. In some embodiments,additional monomers or polymers. In some embodiments, the additionalcomponents may copolymerize with the UDMA and the MMA.

FIGS. 9A-B show an example of components for an adhesive copolymer kit.Both Parts contain the base materials (UDMA and MMA), and Part Acontains the initiators while Part B contains the accelerator. In otherembodiments, one or the other of the Parts may contain the UDMA and/orthe MMA and/or other components in any combination that preventspremature polymerization. This polymeric adhesive hybrid formulationallows for fast curing (120 s) using blue light (450-470 nm) via aphotoinitiator (Camphorquinone), but it also allows for slower curing(5-20 min) due to the thermal/chemical initiator-accelerator combination(Benzoyl Peroxide and N,N-Dimethyl-p-toluidine). Therefore, areas thathave not been adequately exposed to blue light are subsequently fullycured even in the absence of light. A kit may have any amounts ofcomponents described herein.

In some embodiments, a kit may include a syringe having two reservoirsand the syringe may be useful for dispensing an adhesive mixture into abone, joint, or other space or onto a surface (e.g. it may have a needleor nozzle). FIG. 10 shows syringe 70 with a first reservoir with a firstmixture 72, and a second reservoir with a second mixture 74. The syringeincludes a chamber 76 for combining or mixing the contents of the firstand second reservoirs together. In one embodiment, the two parts arepackaged in a two-barrel syringe (25 mL per barrel) and configured to bemixed (mixing ratio 1:1) just before use using a long (8 in) mixingnozzle tip.

In some embodiments, the first mixture defines a viscosity between about1 Pa·s and about 5000 Pa·s, or between about 1000 Pa·s and about 4000Pa·s, or between about 2000 Pa·s and about 3000 Pa·s.

EXAMPLES Example 1

This is a prophetic example. A cartilage replacement material comprisingan interpenetrating polymer network of polyetherurethane and crosslinked sodium polyacrylate was bonded to cancellous bone. Suitablecartilage materials are described, e.g., in U.S. application Ser. No.12/499,041 and in U.S. application Ser. No. 13/219,348, the disclosuresof which are incorporated herein by reference. The adhesive comprisedlow molecular weight polyetherurethane chains (60%), methyl methacrylate(MMA) monomer (30%), an acrylated benzophenone photoinitiator (10%), andhydroquinone (200 ppm). The polyurethane chains are made from ofpoly(tetramethylene oxide) (PTMO), methylene diphenyl diisocyanate(MDI), and hydroxyacrylate (HEA) or hydroxyethyl methacrylate (HEMA).The adhesive (viscous liquid) was applied between the tissue replacementmaterial and the cancellous bone. To cure the adhesive, UV light wasapplied to the adhesive by shining the light through the tissuereplacement material for 10 minutes. The adhesive chemically bonded tothe tissue replacement material and was anchored to the cancellous bonevia penetration into and subsequent solidification within the bonepores.

Adhesive materials according to embodiments of this invention have thecharacteristic advantages of attaining the following characteristicssimultaneously: (1) high tensile and compressive strength, (2) hightensile and compressive modulus, (3) the ability to chemically bond topolyurethane and PMMA substrates, and (4) the ability to fix compliantimplants to bone and other biological tissues through rapid curing withexposure to UV light. An example of said compliant implant is acartilage replacement device or resurfacing prosthesis that takes theplace of damaged articular cartilage in the body and reconstitutes thelow friction, load bearing properties of hyaline cartilage in mammalianjoints. Any joint containing cartilage can be resurfaced with acompliant bearing material anchored with the adhesive described in thisinvention. The adhesive can also be used to anchor replacement materialsfor fibrocartilaginous structures (such as the meniscus) or otherload-bearing structures in the body such as bursae.

Many parameters may be varied when preparing the adhesive compositionsof this invention, such as the conditions of polymerization (i.e.ambient oxygen, UV intensity, UV wavelength, exposure time,temperature), polyurethane constituents, crosslinking density, molecularweight of precursor polymers, and relative weight percent of polymers.

Example 2

Three adhesives were formulated comprising low molecular weightpolyetherurethane chains (60%), methyl methacrylate (MMA) monomer (30%),an acrylated benzophenone photoinitiator (10%), and hydroquinone (200ppm). The polyurethane chains were made from poly(tetramethylene oxide)(PTMO), methylene diphenyl diisocyanate (MDI), and hydroxyacrylate (HEA)or hydroxyethyl methacrylate (HEMA). Adhesive 1 had PTMO 650 MW and PTMO1000 MW of 50%-50%; Adhesive 2 had PTMO 1000 MW 100%; and Adhesive 3 hadPTMO 650 MW 100%.

The tensile properties of Adhesives 1-3 were measured using dogbonesample according to ASTM D638-IV. FIG. 12 shows the tensile modulus at astress of 2 Mpa of the new adhesives, with Adhesive 1 data representedby circles, Adhesive 2 data represented by diamonds, and Adhesive 3 datarepresented by triangles. As shown, addition of MMA increases thetensile stiffness of the adhesive, reaching values as high as 900 MPa.Other formulations can go even higher in stiffness. It also shows thatlower molecular weight (MW) of the polyurethane chains (Adhesive 3)leads to higher stiffness than higher MW chains (Adhesive 2).

FIG. 13 shows the ultimate tensile strength of the new adhesives, withAdhesive 1 data represented by circles, Adhesive 2 data represented bydiamonds, and Adhesive 3 data represented by triangles. As shown,addition of MMA renders the material stronger in tension. Again, lowerMW polyurethane chains tends to yield stronger (higher ultimate tensilestress) materials for MMA content>=30%.

Example 3

A lap shear test was conducted after bonding two sheets of Elasthane 75Dpolyetherurethane using Adhesives 1, 2 and 3 above. As described above,the three different adhesive formulations differ by polyurethane softsegment chemistry (molecular weight MW of PTMO chains). The results areshown in FIG. 14, with Adhesive 1 data represented by circles, Adhesive2 data represented by diamonds, and Adhesive 3 data represented bytriangles. As shown, Adhesive 1, having a mixed MW (50%-50% PTMO 650 MWPTMO 1000 MW) yields superior shear strength.

Example 4

A lap shear test was conducted after bonding a sheet ofpolyetherurethane to cancellous bone with Adhesives 1, 2 and 3 above. Asdescribed above, the three different adhesive formulations differ bypolyurethane soft segment chemistry (molecular weight MW of PTMOchains). The results are shown in FIG. 15, with Adhesive 1 datarepresented by circles, Adhesive 2 data represented by diamonds, andAdhesive 3 data represented by triangles. As shown, shear strengthvalues range from 3-8 MPa with failure usually occurring within the boneitself rather than the adhesive or the adhered material.

Example 5: An Exemplary Synthesis Procedure of the UDMA for OneEmbodiment of the Polymeric Adhesive

The chemical composition of urethane dimethacrylate (UDMA) may betailored to match the polyurethane structure of the anchoring surface ofan IPN or semi-IPN containing material or device. More specifically, insome embodiments, the IPN or semi-IPN containing material or device hasan anchoring surface comprised of Elasthane™ 75D, a medicalpoly-ether-urethane. Elasthane™ 75D is an MDI (4,4-Methylenebis(phenylisocyanate)) based polyurethane that contains PTMO (poly(tetramethyl)glycol) of molecular weight 650 Da as the soft segment and BD(2-Butene-1,4-diol) as the chain extender. In some embodiments, the UDMAin the polymeric adhesive closely matches the structure of Elasthane™75D by employing the same hard and soft segments (FIG. 9). To facilitatecrosslinking, the UDMA is terminated with HEMA (2-Hydroxyethylmethacrylate) (FIG. 9). This similarity between the polymeric adhesiveand Elasthane™ 75D is key to the adhesive capability of polymericadhesive as we hypothesize that hydrogen bonds between the hard segmentsof the Elasthane™ and the polymeric adhesive are formed, developing astrong adhesive force.

UDMA Synthesis Steps (200 g batch). Raw materials used in theformulation of UDMA. MDI, PTMO, and HEMA are obtained fromSigma-Aldrich.

1. Using a 1-liter 3-necked round bottom flask equipped with mechanicalstirring and N₂ purging line, add 0.219 mol pre-dried (at 60° C.overnight in a vacuum oven) MDI. Turn on the N₂ purging, and thensubmerge the flask in a 60° C. water bath. Wait for 30 min to allow theMDI to melt.

2. Add 0.107 mol pre-dried (at 60° C. overnight in a vacuum oven) PTMO(Mw: 650-1000 Da) via an addition funnel over 30 min while maintainingvigorous stirring. If the PTMO freezes in the funnel, heat it up with aheat gun to maintain the addition speed. Continue stirring for 60 minafter adding the PTMO.

3. Add 0.225 mol HEMA via an addition funnel in one batch. Continuestirring for 4 h.

4. At the end of the reaction, add 0.1 wt % of hydroquinone based on thetotal weight of synthesized cement. Stir for 10 min before storing thesynthesized UDMA in the refrigerator.

Example 6: Synthesis of the Polymeric Adhesive

Some embodiments of the polymeric adhesive can be formulated by mixingsynthesized UDMA with the desired amount of MMA and other ingredients,such as initiator and accelerator. The mixing procedure of an examplebased on 30 wt % MMA, 1 wt % camphorquinone (photoinitiator), 1 wt %benzoyl peroxide (thermal initiator), and 1 wt %N,N-dimethyl-p-toluidine (accelerator) formulation(PUA-50-30-CQ1.0-BP1.0-DMPT1.0) [nomenclature used here and throughoutis the following, or based on the following: PUA-% of PTMO 650(remainder is PTMO 1000-% MMA content-photoinitiator-photoinitiatorconcentration (w/w)-thermal initiator-thermal initiator concentration(w/w)-accelerator-accelerator concentration (w/w)-other/optionalconstituent-other/optional constituent concentration-Lot #] is givenbelow:

Part A

a. Add 20 g of synthesized UDMA into a capped 50-mL centrifuge tube.

b. Add 0.596 g camphorquinone (CQ), 0.506 g benzoyl peroxide (BP), and8.935 g MMA into a capped 20-mL glass vial. Gently shake the vial untilthe CQ and BP dissolve completely.

c. Add the MMA mixed with initiators into the centrifuge tube containingUDMA; vigorously stir with a mechanical stirrer for 5 min to ensurethorough mixing.

Part B

d. Weigh 20 g of synthesized UDMA in a capped 50-mL centrifuge tube(tube B).

e. Add 0.596 g N,N-dimethyl-p-toluidine (DMPT) and 8.935 g MMA into acapped 20-mL glass vial. Gently shake the vial until the DMPT dissolvescompletely.

f. Add the MMA mixed with accelerator into the centrifuge tubecontaining UDMA (tube B); vigorously stir with a mechanical stirrer for5 min to ensure thorough mixing.

Packaging

g. Degas both vials using light centrifugation.

h. Slowly pour Part A into one cartridge of the dual syringe and Part Binto the other cartridge. Cap the syringe and install pistons. Wrap thesyringe with aluminum foil and store it upright.

The polymeric adhesive is now ready to use, which can be cured via photoand/or thermal initiation. The polymeric adhesive can be formulated witheither CQ or BP alone, which are the light-cure only or thermo-cure onlyversions, respectively.

Sterilization

As a proof-of-concept, a high-viscosity formulation of one embodiment ofthe polymeric adhesive (PUA-50-30-CQ1.ACC1) has been successfullyfiltered. Using a pressure of approximately 100 psi, the polymericadhesive was passed through a 0.2 μm filter (hydrophilic, Fluoropore,Millipore) at room temperature. The experience was that the filterneeded to be pre-wetted with a low-viscosity polymeric adhesive(PUA-50-60) before filtration could be performed with the higherviscosity formulation. The polymeric adhesive cured after filtration.

Example 7: Curing Duration

As with other orthopaedic and dental cements, the curing dynamics of thedescribed polymeric adhesives can be adjusted by altering theconcentrations of the initiators and accelerators. For curing with bluelight, one embodiment of the polymeric adhesive has been designed tocure within 2 min. For thermal curing, one embodiment of the polymericadhesive has been designed to have doughing (i.e. working) and settingtimes (as defined in ASTM F451-08) in the range seen for PMMA bonecements (FIG. 16). These result in full curing of the polymeric adhesivewithin 20 min without light exposure (see next section). The currentshort working/setting time is desired for some applications, butfinalized surgical instrumentation and procedure may require a longerworking time.

Curing dynamics for several PMMA bone cements and the describedpolymeric adhesive (thermal cure only, no light exposure). The data forCMW, Palacos, and Simplex P were obtained from a CMW brochure [10] andshow times at 18° C. The data for the polymeric adhesive(PUA-50-35-CQ1.1-BP0.95-DMPT1.1) was estimated from a preliminary studyperformed at room temperature (˜23° C.) that did not fully conform tothe test method described in ASTM F451-08. (The values for the polymericadhesive have been estimated from a preliminary study).

Example 8: Conversion Study Using ATR-FTIR

In some embodiments of the polymeric adhesive, the main component isstructurally similar to commercially available UDMA. Thus, the rationaleof conversion calculation for UDMA that was previously reported in theliterature [9] was followed. In the FTIR spectrum, the stretchingabsorption of the vinyl C═C in UDMA and MMA appears at 1637 cm⁻¹ and thestretching absorption of the aromatic C═C in UDMA appears at 1598 cm⁻¹.The aromatic C═C absorbance is used as a standard to which the vinyl C═Cabsorbance is normalized. The conversion is calculated by the followingequation:

${DC} = {\left\lbrack {1 - \frac{\left( {A_{C = C}/A_{Ar}} \right)_{polymer}}{\left( {A_{C = C}/A_{Ar}} \right)_{monomer}}} \right\rbrack \times 100\%}$

where DC is the degree of double bond conversion,(A_(C═C)/A_(Ar))_(polymer) is the ratio of vinyl C═C absorbance toaromatic C═C absorbance in the cured polymeric adhesive, and(A_(C═C)/A_(Ar))_(monomer) is the ratio of vinyl C═C absorbance toaromatic C═C absorbance in the uncured polymeric adhesive.

FIG. 17 shows FTIR spectra of the thermally cured polymeric adhesive atdifferent curing times (0-20 min).

FIG. 17 shows the thermal curing process ofPUA-50-30-CQ1.0-BP0.85-DMPT1.0-Lot#26 at room temperature. Thedisappearance of the vinyl C═C peak over time indicates an increasingconversion. Depending on the baseline correction mode, full spectrumbaseline correction or partial baseline correction, the calculatedconversion differs by about 20% at the end of curing, as shown in FIG.18A. FIG. 18A shows the degree of C═C bond conversion vs. time for thepolymeric adhesive PUA-50-30-CQ1.0-BP0.85-DMPTLO-Lot#26 via only thermalcuring.

Example 9

The conversion of the polymeric adhesive cured by blue light was alsostudied based on this method, using the same polymeric adhesive. Due tothe fast polymerization rate of blue light curing, we only conducted theconversion study on a fully cured sample, which was cured for 2 min. Theresults are summarized in FIG. 18B. FIG. 18B shows the Degree of C═Cconversion of the polymeric adhesivePUA-50-30-CQ1.0-BP0.85-DMPT1.0-Lot#26 cured by blue light. Threetechniques for signal baseline correction (BSL) were evaluated. The fullbaseline correction takes the entire spectrum into account while thepartial baseline correction only uses a region of the spectrum.

Example 10: Leaching Properties

A leachables analysis was conducted on some embodiments of the polymericadhesive samples, and results were compared to samples of Stryker®Simplex® P PMMA bone cement. Samples were incubated in ultrapure waterand leachables were evaluated by measuring the carbon and nitrogencontent in the water with a TOC/TC machine. Following the rationale ofASTM F451-08, samples were made in a mold so that leaching could onlyoccur from one surface of defined surface area. To simulate a worst-casescenario, the polymeric adhesive samples (PUA-50-30-CQ1.3-DMPT1.0) (n=2)were placed in the ultrapure water before blue light curing (2 min).After mixing the Simplex® P according to the manufacturer'srecommendations, samples (n=2) were placed in the molds and submerged inultrapure water 4 min after mixing began. Because MMA monomer is themain leachable for PMMA bone cement, and theoretically the mainleachable for the polymeric adhesive, the amount of leached MMA monomerwas calculated from the carbon content of the ultrapure water, assumingall carbon was from MMA. In addition, to remove volatiles from thesolutions (i.e., MMA monomer), solutions were dried in an oven andremaining carbon and nitrogen were re-dissolved in ultrapure water. Thecarbon and nitrogen content was determined and compared to the initialmeasurements to determine amount of volatiles in the leachables.

FIG. 19A shows carbon and nitrogen leachables in ultrapure water over 7days. Nitrogen leaching approached the detection limit of themeasurement system. The polymeric adhesive formulation wasPUA-50-30-CQ1.3-DMPT1.0. FIG. 20B shows maximum MMA monomer release over7 days. This calculation assumes that all carbon was MMA. The highernon-volatile carbon leachables in the polymeric adhesive (FIG. 19B)suggests that this plot shows an overestimation of MMA release for thepolymeric adhesive. The polymeric adhesive formulation wasPUA-50-30-CQ1.3-DMPT1.0. FIG. 21 shows volatile and non-volatilecomponents of carbon leachables. For the polymeric adhesive samples, thenon-volatile carbon was always less than 37% of the total carbon, whilefor Simplex® P samples the non-volatile carbon was always less than 12%of the total carbon. These results indicate that MMA monomer was themain leachable in both materials. The polymeric adhesive formulation wasPUA-50-30-CQ1.3-DMPT1.0.

The described polymeric adhesive leached approximately 40-50% lesscarbon and MMA monomer than Simplex® P bone cement (FIGS. 20A-B). Theseresults for Simplex® P fall within the range of MMA monomer releasereported in the literature [6-7]. In contrast to carbon, the polymericadhesive leached up to 60% more nitrogen than Simplex® P (FIG. 19A).However, cumulative nitrogen leaching for the polymeric adhesive sampleswas only 0.040 mg per 1.25 g sample. For the polymeric adhesive samples,the non-volatile carbon was always less than 37% of the total carbon,while for Simplex® P samples the non-volatile carbon was always lessthan 12% of the total carbon (FIG. 20). These results indicate that MMAmonomer was the main leachable in both materials and that the polymericadhesive had a larger component of leachables that were not MMA, whichis likely to be initiator (camphorquinone).

Example 11: Oxidative Stability

Accelerated biostability testing of the polymeric adhesive. Compared tocontrol samples, changes in dry mass were not statistically differentfor either oxidative stability samples (p=0.058) or hydrolytic stabilitysamples (p=0.307). One set of control samples were used for bothoxidative and hydrolytic stability tests.

Accelerated biostability testing was conducted following ISO 10993-13.As a screening test for evaluating oxidative stability, we choseharsher, more accelerated conditions than those recommended in the ISOstandard. The ISO-recommended accelerated oxidative stability testinvolves incubating the samples in 3% hydrogen peroxide at an elevatedtemperature for 60 days. To further accelerate the test, we incubatedpolymeric adhesive (PUA-50-30-CQ1.0-EDMAB1.0 [EDMAB=Ethyl4-(dimethylamino)benzoate]) samples (n=3) in 30% hydrogen peroxide at52° C. for 14 days (solutions were changed twice per week). Changes indry mass were compared with changes for control samples (n=3) that weremaintained in phosphate buffered saline (PBS, pH 7.4) at 52° C. for 14days. All samples were equilibrated in PBS before drying for massmeasurements.

As can be seen in FIG. 21, samples exposed to these oxidative conditionsshowed a slight decrease in mass. Compared with control samples, thechange in dry mass was approaching statistical significance (p=0.058).These slight changes in dry mass under highly accelerated oxidationconditions support the oxidative stability of the polymeric adhesive.

Example 12: Hydrolytic Stability

As a screening test for evaluating hydrolytic stability, we again choseharsher, more accelerated conditions than those recommended in the ISO10993-13 standard. The ISO-recommended accelerated hydrolytic stabilitytest involves incubating the samples in PBS at an elevated temperaturefor 60 days. To further accelerate the test, we incubated polymericadhesive (PUA-50-30-CQ1.0-EDMAB1.0) samples (n=3) in a basic salinesolution at pH 10.6 (OH⁻ ions induce hydrolysis, so every increase in pHof 1.0 should increase the hydrolysis rate by 10) at 52° C. for 14 days.Theoretically, these incubation conditions are the equivalent of over170 years at body temperature and pH. Changes in dry mass were comparedwith changes for control samples (n=3) that were maintained in phosphatebuffered saline (PBS, pH 7.4) at 52° C. for 14 days. All samples wereequilibrated in PBS before drying for mass measurements.

As can be seen in FIG. 21, samples exposed to these hydrolyticconditions showed a slight decrease in mass. The change in dry mass wasnot statistically different than the change for control samples(p=0.307). This result under accelerated hydrolytic conditions supportsthe hydrolytic stability of the polymeric adhesive.

Example 13: Biocompatibility Testing

The ISO cytotoxicity test (ISO 10993-5) was conducted on the followingpolymeric adhesive formulation: PUA-50-30-CQ1.0-EDMAB1.0. A plate ofpolymeric adhesive was cured under blue light for 2 min. Thecytotoxicity test (24 h extraction at 37° C. in serum-supplemented MEMsolution) showed a score of 0 after 48 h, indicating no cytotoxicity(0=non-cytotoxic, 4=highly cytotoxic) [8].

Example 14: Mechanical Properties

FIG. 22 shows a summary of the mechanical properties of the polymericadhesive (PUA-50-35). Values obtained from [2-7].

The polymeric adhesive technology was invented to attach IPN or semi-IPNcontaining materials or devices to bone. The mechanical properties ofthe polymeric adhesive have been engineered to meet the biomechanicalrequirements for a joint replacement device (FIG. 22). The compressiveand tensile stiffness have been tuned to form a bridge betweencancellous bone and the anchoring surface of IPN or semi-IPN containingmaterials or devices. The failure strain has also been engineered to behigh enough to allow for the finite deformations of the compliant IPN orsemi-IPN containing materials or devices without cracking. The adhesionstrength to IPN or semi-IPN containing materials or devices anchoringsurfaces, measured using peel tests, approaches the tear strength of theIPN or semi-IPN containing materials or device itself, signifying asecure bond between the device and the cement that limits relativemicromotion. In addition, the interfacial bond strength to bone,measured in lap-shear tests, is comparable to the bond strength achievedby PMMA bone cement, which are both higher than the strength of boneitself. Furthermore, the polymeric adhesive is a crosslinked materialthat has excellent creep properties. In all these aspects, themechanical properties of the polymeric adhesive are comparable to orexceed those of conventional PMMA bone cement, rendering the polymericadhesive a viable method for IPN or semi-IPN containing materials ordevices attachment.

Mechanical Testing Methods

Example 15: Tensile Testing

FIG. 23A shows a schematic of the tensile test setup. FIG. 23B showstypical true stress—true strain tensile plot for a polymeric adhesiveformulation (PUA-100-35-CQ1.15-BP0.98-DMPT1.15). Elastic modulus at 2MPa is found by taking the tangent over the stress range of 2±0.75 MPa.

Tensile testing for the polymeric adhesive was performed. Samples wereprepared by curing plates of the polymeric adhesive between two glassplates, using spacers for even thickness. Using a cutting die, thepolymeric adhesive plates were cut into dumbbell shaped samples fortesting. After a period of incubation at 37° C. in PBS, samples weretested using the tensile grips of the mechanical tester. Samples werepulled in tension at a rate of 4.064 mm/s until failure in a 37° C.water bath. Data analysis yielded stress-strain curves, tensile moduli,tensile strength and ultimate tensile strain for the tested samples.FIGS. 23A-B shows the tensile test setup and a typical stress-straincurve for the polymeric adhesive PUA-100-35.

Example 16: Compressive Testing

FIG. 24A shows a schematic of the compression (unconfined) test setup.FIG. 24B shows a typical stress—strain curve forPUA-50-35-CQ1.11-BP0.95-DMPT1.11. The elastic modulus was found to be231 MPa.

Example 17: Creep Testing

FIG. 25A: Schematic of the compressive creep (unconfined) test setup.FIG. 25B: A typical compressive creep curve for the polymeric adhesive(PUA-50-35-C1.11-BP0.95-DMPT1.11) sample over a 22 h period.

Compressive creep testing for one embodiment of the polymeric adhesive.Samples were prepared by curing the polymeric adhesive in 5-mL culturetubes, and then using a lathe to machine the samples into cylinders of12.5±0.25 mm in thickness and 9.5±0.25 mm in diameter. After a period ofincubation at 37° C. in PBS, samples were tested using the compressionplatens of the mechanical tester. Samples were loaded at a rate of 10N/s to a maximum holding stress of 2.7 MPa. This stress was held for 22h to monitor the creep properties of the material. After the creep testwas completed, the stress was relieved to a 5 N load at a rate of 10N/s. The 5-N load was held for 30 min before the sample was measured forcompression set (residual strain at 30 min). Each sample remainedunloaded in an incubation chamber for at least 24 h before beingmeasured for permanent creep (residual strain at 24 h). FIG. 26A showsthe compressive creep test setup and a typical creep response forPUA-50-35-CQ1.11-BP0.95-DMPT1.11.

Example 18: Peel Testing

FIGS. 26A-B show the peel test preparation fixture used to make testcoupons assembled (FIG. 26A) and disassembled (FIG. 27B) for clarity.

FIGS. 27A-B show schematics of the peel test setup. FIG. 27A: A typicalpeel test of the polymeric adhesive (PUA-100-35.CQ1.15-BP0.98-DMPT1.15)adhered between two micro-roughened Elasthane™ 75D (polyurethane)coupons. The arrow points at the peak (peel initiation) strength, whilethe dashed line represents the average peel propagation strength.

Peel testing for one embodiment of the polymeric adhesive was performed.Using the T-Test peel method, we evaluated the peel strength (forcerequired to peel per unit width) required to initiate a peel (peelinitiation strength) and to propagate the peel (peel propagationstrength). Samples were prepared using a custom peel sample preparationfixture (FIGS. 26A-B). IPN or semi-IPN containing coupons were securelyplaced on each side of a slotted groove creating a confined cavitybetween the coupons, with only one opening for polymeric adhesiveinjection. The IPN or semi-IPN containing coupons were compressedbetween two glass plates using clamping clips. Then, polymeric adhesivewas injected into the opening between the coupons (FIG. 26B). Once thecavity was filled with the polymeric adhesive, the sample was cured andthen removed from the fixture. Inventors developed this preparationsystem in order to ensure every peel sample had a consistent polymericadhesive width, length and thickness (3.175 mm, 30 mm and 2 mm,respectively) that conform (proportionally) to the ASTM standard. Thisconfined area of the polymeric adhesive reduces the tearing of IPN orsemi-IPN containing coupons by increasing the IPN or semi-IPN containingmaterial-to-polymeric adhesive ratio as well as minimizes excesspolymeric adhesive flash from the intended test area. After a period ofincubation at 37° C. in PBS, samples were setup and tested using thetensile grips of the mechanical tester (FIGS. 27A-B). The unadhered endsof the sample were placed into each tensile grip, creating a 90 degreeangle between the axis of the grips and the adhered end of the sample.Samples were pulled in tension at a rate of 4.23 mm/s until peeling wascomplete. Data analysis yielded the peak and propagation peel strengthsfor each sample.

Example 19: Bone Lap-Shear Testing

FIG. 28 shows a schematic of the bone lap-shear test setup.

Bone lap-shear testing was performed in accordance with ASTM D3163.Samples were prepared by curing polymeric adhesive between a coupon ofcancellous bone (taken from the bovine distal femur) and a coupon ofpolyurethane, both of the same width. Special attention was given increating loading conditions that would only subject the coupons toshear. Therefore, a linear bearing system was employed that ensured onlyaxial movement of the bone relative to the IPN or semi-IPN containingcoupon. In addition, due to initial bone failures (tensile failure) anend support was added to the feature so that bone would be compressedrather than tensioned. The entire system was mounted on the universaltesting system using the tensile grips.

The samples were cured and incubated at 37° C. before testing. Using thetensile grips of the mechanical tester, the unadhered ends of the samplewere placed in the upper and lower grips. The samples were then pulledin tension at a shear rate of 0.15±0.1 MPa/s until failure. Dataanalysis yielded the maximum shear stress for each sample.

Example 20: Viscosity Testing

FIG. 29 shows viscosity-time profile of polymeric adhesive(PUA-50-30-CQ1.0-DMPT1.0 (light cure only)) at 23° C. Typicalthixotropic behavior of polymeric adhesive is observed in this chart. Asthe cement is subjected to a constant shear rate, the viscosity profiledecreases over time.

Viscosity testing for the polymeric adhesive was performed using aBrookfield HBTCP Dial Viscometer. Each polymeric adhesive formulationwas loaded into a 3-mL syringe (with a 0.5 mL resolution) by injectingthe polymeric adhesive from a double-barrel syringe directly into theback of the sample syringe. No thermal initiator was added to this batchof polymeric adhesive to prevent curing while testing the polymericadhesive. Each sample syringe was then capped to prevent exposure to airand wrapped in aluminum foil to prevent exposure to ambient lighting.Each sample syringe was placed in a temperature-regulated environmentthat matched the desired testing temperature for at least 12 h, allowingtime for temperature equilibrium and any material restructuring requiredduring the equilibrium process.

To perform testing, 0.5 mL of the polymeric adhesive was dispensed fromthe syringe to the center of the viscometer sample cup. The sample wasthen left for 45-60 minutes in the sample cup to allow it to furtherequilibrate to the desired testing temperature. All polymeric adhesiveformulations were subjected to testing at 18° C., 23° C., and 37° C. Thespeed of the viscometer was dependent on the viscosity of the sample,ranging from 0.5 RPM to 20 RPM. Higher viscosity samples required higherRPM. Due to the thixotropic properties of the polymeric adhesive(decreasing viscosity at a constant shear rate over time), measurementswere made every 30 s for 8 min as shown in FIG. 30. The average of thesixteen measurements was reported as the viscosity of the polymericadhesive formulation at the specific temperature. Viscosity for thepolymeric adhesive is reported in Pascals per second (Pa-s).

Mechanical Properties as a Function of Material Composition

FIG. 30 shows elastic modulus of the polymeric adhesive versus theMMA-content in the final material. These data points were obtained fromthe following polymeric adhesive formulations (in order from left toright):

PUA-50-30-CQ1.0-BP0.85-DMPT1.0,

PUA-50-35-CQ1.11-BP0.95-DMPT1.11,

PUA-50-40-CQ1.22-BP1.04-DMPT1.22

The described polymeric adhesive is designed to bridge the stiffnessmismatch between the compliant IPN or semi-IPN containing device and thecancellous bone to which it is anchored. Using the information fromthese measurements, the right formulation can be selected to bettermatch the product specs.

An MMA-content in the range of 35% for some orthopedic implants issuggested in terms of compressive properties.

Example 21: Hardness (Shore D) vs MMA %

FIG. 31 shows polymeric adhesive hardness (Shore D) versus theMMA-content.

Similar to the compressive stiffness, polymeric adhesive hardnessincreases with increasing MMA-content (FIG. 32). The polymeric adhesivewas cured inside OD=10 mm polypropylene cylinders, and then weremachined transversely flat on a vertical mill. A digital durometer wasthen used to measure hardness.

As can be seen in FIG. 31, the higher the MMA-content, the more thematerial resembles PMMA. Accordingly, the lower the MMA-content, themore the material resembles pure UDMA.

Example 22

FIG. 32 shows creep recovery after 22 h of loading at 2.7 MPa. The datashow the remaining strain at 0 min, 30 min, and 24 h after the 2.7 MPaload has been removed and the sample was allowed to recover itsthickness. Data for three polymeric adhesive are shown (from left toright: PUA-50-30-CQ1.0-BP0.85-DMPT1.0, PUA-50-35-CQ1.11-BP0.95-DMPT1.11,and PUA-50-40-CQ1.22-BP1.04-DMPT1.22).

It is important for a bone cement to maintain good creep properties forthe working tolerances of a compliant cartilage replacement to bemaintained. The described polymeric adhesive is a crosslinked materialthat recovers very well after the load is removed. One important notehere has to be made on the time to recover. The described polymericadhesive presents a rather large viscoelastic time constant, which meansthat it takes a long time to reach the equilibrium strain when acompressive load is applied and to relax upon load removal. FIG. 32shows the creep recovery behavior for various polymeric adhesiveformulations.

An MMA content of 30%-35% is suggested for some medical implants.

Example 23: Peel Strength vs. MMA %

FIGS. 33A-B show peel initiation (FIG. 33A) and peel propagation (FIG.33B) strength for smooth Elasthane™ 65D plates and five polymericadhesive formulations (In order from left to right:PUA-50-25-CQ0.88-BP0.73-DMPT0.88, PUA-50-30-CQ1.0-BP0.85-DMPT1.0,PUA-50-35-CQ1.11-BP0.95-DMPT1.11, PUA-50-40-CQ1.22-BP1.04-DMPT1.11, andPUA-50-45-CQ1.41-BP1.2-DMPT1.41).

Peel properties are probably the most efficient method to qualify anadhesive. The described polymeric adhesive demonstrates high peelstrength, both at the initiation level and at the propagation level.FIGS. 33A-B demonstrate the peel properties of the described polymericadhesive on smooth Elasthane™ 65D (used here as a proxy for Elasthane™75D that comprises the anchoring surface of IPN or semi-IPN containingmaterials or devices). MMA % had no significant effect on peel strengthin the 30-40% MMA-content range.

FIGS. 34A-B show peel initiation (FIG. 35A) and peel propagation (FIG.34B) strength for an IPN or semi-IPN containing acetabular device forthree polymeric adhesive formulations (In order from left to right:PUA-50-30-CQ1.0-BP0.85-DMPT1.0, PUA-50-35-CQ1.11-BP0.95-DMPT1.11, andPUA-50-40-CQ1.22-BP1.04-DMPT1.11).

Peel tests were also conducted on the anchoring surface of IPN/semi-IPNdevices which showed a high peel strength, as shown in FIGS. 34A-B.Nonetheless, we have the goal of reaching a peel strength equal to thetear strength of the IPN or semi-IPN containing material itself (approx.30 N/mm), so additional ways to increase peel strength are of interest.

No significant difference was observed within the 30%-40% MMA-contentspan. MMA-content in the range of 30%-40% is suggested for some medicalimplants.

Example 24: Viscosity vs. MMA %

FIG. 35 shows another set of viscosity-MMA % profiles for the polymericadhesive (PUA-50-30-CQ1.0-DMPT1.0) at 18° C., 23° C., and 37° C.performed after refinements were made to the materials and/or testprocesses. See also FIG. 14 and FIG. 15.

From the wide range of viscosities available with different polymericadhesive formulations, the optimal viscosity range lies between 20% and40% MMA-content for some embodiments. In some embodiments, outside ofthis MMA-content range viscosities are not functionally viable for somearthroplasty applications (either too viscous to inject or too runny touse). In evaluating viscosity, relationships between temperature andviscosity and MMA-content and viscosity were determined.

For reference: OR temperature is approximately 18° C., room temperatureis 23° C., open incision temperature is 34° C., and body (core)temperature is 37° C.

Generally, there is an inverse relationship between temperature andviscosity, where an increasing temperature results in lower viscosities.Similarly, an inverse relationship between MMA-content and viscosity hasbeen established, in which more MMA in the polymeric adhesiveformulation yields lower viscosities. Results for polymeric adhesive notcontaining the thermal initiator (thermal initiator would cause instantpolymerization and viscosity values could not be measured effectively)are shown in FIG. 36.

To optimize surgical handling for some medical implants (e.g. orthopedicimplants), a viscosity in the range of 10-100 Pa-s is desirable andrange of MMA % within 30-35% is suggested.

Example 25

Peel Strength vs. Surface Roughness FIG. 36 shows a comparison of peelpropagation strength for a smooth and a roughened Elasthane™ 65Dsurface, using two different polymeric adhesive formulations(PUA-50-35-CQ1.11-BP0.95-DMPT1.11 and PUA-50-40-CQ1.22-BP1.04-DMPT1.22).

Adding roughness to the adhesion surfaces greatly increases the peelstrength as it provides more surface area for molecular interaction aslong as the wettability of the cement is maintained. Smooth Elasthane™65D plates were sanded to a roughness of approximately R_(a)=200 μm andtested in a peel test. As expected, the adhesion force was significantlyincreased (almost doubled). Therefore, adding roughness to the anchoringsurface of the IPN or semi-IPN containing devices is recommended. FIG.36 demonstrates the differences between rough and smooth coupongeometries.

For reference, initial tests with roughened Elasthane™ 75D showed a peakpeel strength in the 30-40 N/mm range while the peel propagationstrength reached approximately 20 N/mm. These values are approaching thetear strength of IPN or semi-IPN containing devices or materials itself.

Add a bi-level roughness profile to the anchoring surface of IPN orsemi-IPN containing materials or devices may improve the adhesionproperties: a macro-roughness of approximately R_(a)=100-200 μm with anadditional micro-roughness of 10-20 μm for some medical implants. It ishypothesized that this bi-level roughness will ensure that the surfaceavailable for adhesion is maximized.

Example 26: An IPN or Semi-IPN Containing Device's Surface Preparationvs. Peel Strength

FIG. 37 shows a polymeric adhesive PUA-50-30-CQ1.0-EDMAB1.0 (light cureonly) to PU (Elasthane™ 80A and 65D) peel strength for various PUsurface preparation solutions. PU samples were swiped with the indicatedsolution. The acetone primed samples did not really peel, but rathertore, so no average value is recorded. Note that average peel strengthis reported in this test (not propagation peel strength). FIG. 38 showstesting of polymeric adhesive PUA-50-30-CQ1.0-EDMAB1.0 (light cure only)on IPN or semi-IPN containing coupons without any acetone treatment (0swipes) produced a relatively low propagation peel strength. However,swiping with acetone resulted in an almost five-fold increase inpropagation peel strength. No significant change was seen when moreswipes were performed.

FIG. 39 shows the peel strength of the described polymeric adhesivePUA-50-30-CQ.10-EDMAB1.0 (light cure only) to the IPN or semi-IPNcontaining material was dependent on the way acetone was applied to thecoupons. Subjecting the coupons to a single swipe of acetone providedthree to five times higher peel strength than simply soaking the couponsin acetone for 20 min.

The adhesion of described polymeric adhesive to poly-ether polyurethanes(PU), such as an IPN or semi-IPN containing anchoring surface, can beincreased by swiping the PU surface with acetone. It was found by peeltests that PU strips swiped with acetone showed >100% higher peelstrength than those swiped with water, ethanol, 70% IPA, or 91% IPA, asshown in FIG. 37.

Another factor that may affect the adhesion to PU is the actual act ofswiping the surface itself. As shown in FIG. 39, the propagation peelstrength of the PU surface swiped with acetone is almost five timeshigher than for a sample simply soaked in acetone (no swiping).

Given that acetone is a better swelling solvent for PU than water,ethanol, or IPA, it is hypothesized that the higher peel strength may bedue to the morphological change on PU surfaces that is induced bypartial swelling with acetone. The surface of PU becomes momentarilyslightly swollen, and the mobility of polymer chains is increased.Further, these more mobile chains are somehow aligned by the swipingprocess and, thus, the acetone swiping process leads to an increase ofthe bonding between PU and the described polymeric adhesive. Thisphenomenon appears to fully occur with one swipe as swiping ten timesdid not improve the peel strength over swiping one time (FIG. 39).

Although the action mechanism is not well understood, mechanical swipingof the anchoring surface of IPN or semi-IPN containing materials ordevices with acetone prior to implantation is suggested for someembodiments.

Example 27

Hardness vs. PTMO Molecular Weight FIG. 40 shows polymeric adhesiveHardness versus polyol (PTMO) molecular weight contribution. The x-axisshows the percentage of PTMO 650 in the formulation of polymericadhesive UDMA, the rest being PTMO 1000. From left to right, thepolymeric adhesive constituents are as follows:PUA-00-35-CQ1.1-BP0.95-DMPT1.1, PUA-50-35-1.11-BP0.95-DMPT1.11,PUA-100-35-CQ1.15-BP0.98-DMPT1.15.

In the described polymeric adhesive, PTMO polyol is the soft segment ofthe UDMA component. PTMO comes in various molecular weights. Elasthane™75D and Elasthane™ 65D use PTMO of molecular weight 650 Da whileElasthane™ 55D uses PTMO of molecular weight 1000 Da. We hypothesizedthat matching the PTMO molecular weight of Elasthane™ 75D would resultin optimal adhesion between the polymeric adhesive and the anchoringsurface of the IPN or semi-IPN containing materials or device. Theadhesive and stiffness characteristics of the polymeric adhesive wereexplored for the two PTMO molecular weights. In general, the higher themolecular weight of the PTMO, the softer the material as there is morew/w soft segment material (FIG. 30). If the molecular weight of the PTMOis too high, solidification of the UDMA will occur. The followingbatches were made and tested:

polymeric adhesive containing 0% PTMO 650 and 100% PTMO 1000

polymeric adhesive containing 50% PTMO 650 and 50% PTMO 1000

polymeric adhesive containing 100% PTMO 650 and 0% PTMO 1000.

Example 28: Tensile Modulus and Strength vs. PTMO Molecular Weight

FIG. 41 shows tensile modulus of polymeric adhesive (at 2 MPa) versusPTMO molecular weight contribution. The x-axis shows the percentage ofPTMO 650 in the formulation of polymeric adhesive UDMA, the rest beingPTMO 1000. From left to right, the polymeric adhesive formulations areas follows: PUA-00-35-CQ1.1-BP0.95-DMPT1.1,PUA-50-35-CQ1.11-BP0.95-DMPT1.11, PUA-100-35-CQ1.15-BP0.98-DMPT1.15.

FIGS. 42A-B show another set of results for ultimate Engineering Strain(FIG. 42A) and Ultimate Engineering Stress (FIG. 42B) of the polymericadhesive versus PTMO molecular weight contribution performed afterrefinements were made to the processes. See also FIG. 12. The x-axisshows the percentage of PTMO 650 in the formulation of the describedpolymeric adhesive UDMA, the rest being PTMO 1000. From left to right,the polymeric adhesive formulations are as follows:PUA-00-35-CQ1.1-BP0.95-DMPT1.1, PUA-50-35-CQ1.11-BP0.95-DMPT1.11,PUA-100-35-CQ1.15-BP0.98-DMPT1.15.

The molecular weight of the PTMO used in the formulation of thedescribed polymeric adhesive has a profound impact on the tensileproperties of the final material. The lower the molecular weight, thestiffer the material is in tension (FIG. 40). The polymeric adhesive hasbeen formulated as a mix of PTMO 650 and PTMO 1000 or simply containingone or the other. As shown in FIG. 41, the tensile modulus may vary byalmost four-fold between the all-PTMO 650 formulation and the all-PTMO1000 formulation. However, the all-PTMO 650 formulation is more brittle,as its ultimate strain (engineering) is less than half that of theall-PTMO 1000 formulation (FIG. 41). In contrast, tensile strength wasnot significantly affected by PTMO molecular weight (FIG. 41).

A PTMO molecular weight of 650 at 50% or more of the total PTMO issuggested to maintain sufficient stiffness and failure properties forsome medical implants.

Example 29: Peel Strength vs. PTMO Molecular Weight

FIGS. 43A-B show polymeric adhesive peak peel initiation (FIG. 43A) andpeel propagation (FIG. 43B) strength versus the PTMO molecular weightcontribution. The x-axis shows the percentage of PTMO 650 in theformulation of polymeric adhesive UDMA, the rest being PTMO 1000. Fromleft to right in each chart, the polymeric adhesive constituents are asfollows: PUA PUA-00-35-CQ1.1-BP0.85-DMPT1.1,PUA-50-35-CQ1.11-BP0.95-DMPT1.11, PUA-100-35-CQ1.15-BP0.98-DMPT1.15.

As mentioned previously, some IPNs or semi-IPNs contain Elasthane™ 75D,which consists of PTMO of molecular weight 650 Da. The adhesiveproperties of the described polymeric adhesive were explored for the twoPTMO molecular weights of 650 and 1000 Da. The following batches weremade and tested for adhesion to smooth Elasthane™ 65D (which containsPTMO 650); results are presented in FIGS. 43A-B:

polymeric adhesive containing 0% PTMO 650 and 100% PTMO 1000(PUA-00-35-CQ1.1-BP0.85-DMPT1.1)

polymeric adhesive containing 50% PTMO 650 and 50% PTMO 1000(PUA-50-35-CQ1.11-BP0.95-DMPT1.11)

polymeric adhesive containing 100% PTMO 650 and 0% PTMO 1000(PUA-100-35-CQ1.15-BP0.98-DMPT1.15).

No significant differences in peel strength were observed when varyingPTMO 650 and PTMO 1000 content under these test conditions. Theseresults suggests that any concentration of PTMO 650 and 1000 may beuseful some medical (e.g. orthopedic) implants.

Example 30: General

FIG. 44 shows a summary of the MMA content parametric studies of variousproperties of adhesive copolymers made using different amounts of MMAmonomer, including results presented above. Dark shaded areas indicateamounts of MMA in adhesive compositions that may be particularly usefulfor some orthopedic implants. Light shaded areas indicate other testedcompositions that may be useful for other applications. Overall,approximately 35% MMA content may be optimal for some medical(orthopedic joint) implants.

Current data suggest that modulus may be the only parameter that issubstantially affected by PTMO molecular weight. All things being equal,it may be advantageous to have the PTMO in the described polymericadhesive match that in the device, namely PTMO 650 in one particularembodiment.

REFERENCES

-   [1] Charnley J. (1972) Acrylic Cement in Orthopaedic Surgery.    Edinburgh, London: Churchill Livingstone.-   [2] Morgan E F et al. (2001). Dependence of yield strain of human    trabecular bone on anatomic site. J Biomech 34:569-577.-   [3] Ohman C et al. (2007). Mechanical testing of cancellous bone    from the femoral head: Experimental errors due to off-axis    measurements. J Biomech 40:2426-2433.-   [4] Lewis G (1997). Properties of acrylic bone cement: State of the    art review. JBMR 38:155-182.-   [6] Puska M A et al. (2005). Exothermal characteristics and release    of residual monomers from fiber-reinforced oligomer-modified acrylic    bone cement. J Biomat App 20:51-64.-   [7] Simplex™ P Bone Cement, Stryker Orthopaedics (Mahwah, N.J.).    Product Literature LSB Rev. 3, 2006.-   [9] Barszczewska-Rybarek (2012). Journal of Applied Polymer Science,    Vol. 123, 1604-1611.-   [10] Bone Cement Time Setting Chart, DePuy Orthopaedics (Warsaw,    Ind.),    http://www.depuy.com/sites/default/files/products/files/DO_Bone_Cement_Setting_Time_Chart.pdf.-   [11] Orr J F, Dunne N J, Quinn J C. (2003). Shrinkage stresses in    bone cement. Biomaterials 24(17):2933-40.-   [12] Kwong F N, Power R A. (2006). A comparison of the shrinkage of    commercial bone cements when mixed under vacuum. J Bone Joint Sung    Br. 88(1):120-2.

As for additional details pertinent to the present invention, materialsand manufacturing techniques may be employed as within the level ofthose with skill in the relevant art. The same may hold true withrespect to method-based aspects of the invention in terms of additionalacts commonly or logically employed. Also, it is contemplated that anyoptional feature of the inventive variations described may be set forthand claimed independently, or in combination with any one or more of thefeatures described herein. Likewise, reference to a singular item,includes the possibility that there are plural of the same itemspresent. More specifically, as used herein and in the appended claims,the singular forms “a,” “and,” “said,” and “the” include pluralreferents unless the context clearly dictates otherwise. It is furthernoted that the claims may be drafted to exclude any optional element. Assuch, this statement is intended to serve as antecedent basis for use ofsuch exclusive terminology as “solely,” “only” and the like inconnection with the recitation of claim elements, or use of a “negative”limitation. Unless defined otherwise herein, all technical andscientific terms used herein have the same meaning as commonlyunderstood by one of ordinary skill in the art to which this inventionbelongs. The breadth of the present invention is not to be limited bythe subject specification, but rather only by the plain meaning of theclaim terms employed.

What is claimed is:
 1. A device comprising: an orthopedic joint implantcomprising a polyurethane IPN or polyurethane semi-IPN; and a urethanedimethacrylate-methyl methacrylate copolymer attached to thepolyurethane IPN or polyurethane semi-IPN, the urethanedimethacrylate-methyl methacrylate copolymer comprising a plurality offirst polymer regions based on urethane dimethacrylate and a pluralityof second polymer regions based on methyl methacrylate, wherein theplurality of first polymer regions based on urethane dimethacrylatecomprises a plurality of hard segments and soft segments.
 2. The deviceof claim 1, wherein the urethane dimethacrylate-methyl methacrylatecopolymer is attached to the polyurethane IPN or polyurethane semi-IPNby a non-covalent interaction between the urethane dimethacrylate-methylmethacrylate copolymer and the polyurethane IPN or polyurethanesemi-IPN.
 3. The device of claim 1, wherein the first polymer regionsbased on urethane dimethacrylate comprise about 60%-99% (w/w) of thecopolymer and the second polymer regions based on methyl methacrylatecomprise about 1%-40% (w/w) of the copolymer.
 4. The device of claim 1,wherein the first polymer regions based on urethane dimethacrylatecomprise about 60%-80% (w/w) of the copolymer and the second polymerregions based on methyl methacrylate comprise from about 20%-40% (w/w)of the copolymer.
 5. The device of claim 1, wherein the hard segment ofthe first polymer region based on urethane dimethacrylate comprises oneor more of: 1,5 napthalene diisocyanate (NDI), 2,6 toluene diisocyanateor 2,4 toluene diisocyanate (TDI), 3,3-bitoluene diisocyanate (TODI),cyclohexyl diisocyanate (CHDI), hexamethyl diisocyanate (HDI),isophorone diisocyanate (IPDI), methylene bis(p-phenyl) isocyanate,methylene diphenylisocyanate (MDI), and methylene bis (p-cyclohexylisocyanate (H12MDI).
 6. The device of claim 1, wherein the soft segmentof the first polymer region based on urethane dimethacrylate comprisesone or more of: polybutadiene, polyethylene oxide (PEO), hydroxyterminated butadiene, hydroxybutyl terminated polydimethylsiloxane(PDMS), hydroxyl terminated polyisobutylene, poly (1,6 hexyl 1,2 ethylcarbonate), polycaprolactone, polycarbonate, polyethylene adipate,polyhexamethylene carbonate glycol, polypropylene oxide (PPO),polytetramethylene adipate, poly(dimethylsiloxane), andpoly(tetramethylene oxide) (PTMO).
 7. The device of claim 1, wherein thefirst polymer regions based on urethane dimethacrylate comprise softsegments based on poly(tetramethyl) glycol, the soft segments having amolecular weight between about 100 Da and about 5000 Da.
 8. The deviceof claim 1, wherein the hard segment of the first polymer region basedon the urethane dimethacrylate comprises methylene diphenylisocyanate(MDI) and the soft segment of the first polymer region based on theurethane dimethacrylate comprises poly(tetramethylene oxide) (PTMO). 9.The device of claim 1, wherein the urethane dimethacrylate-methylmethacrylate copolymer defines a compressive modulus between about 30MPa and about 2000 MPa.
 10. The device of claim 1, wherein the urethanedimethacrylate-methyl methacrylate copolymer defines a tensile modulusbetween about 30 MPa and 2000 MPa.
 11. The device of claim 1, whereinthe urethane dimethacrylate-methyl methacrylate copolymer defines afailure strain between about 25% and about 200%.
 12. The device of claim1, further comprising: a radiopaque material.